Potent PARP Inhibitors

ABSTRACT

The present invention relates to 1H-benzimidazole-4-carboxamides of formula (I),  
                 
their preparation, and their use as inhibitors of the enzyme poly(ADP-ribose)polymerase for the preparation of drugs.

This application claims priority to the provisional application Ser. No.60/805,235 filed on Jun. 20, 2006.

TECHNICAL FIELD

The present invention relates to 1H-benzimidazole-4-carboxamides, theirpreparation, and their use as inhibitors of the enzymepoly(ADP-ribose)polymerase for the preparation of drugs.

BACKGROUND

Poly(ADP-ribose)polymerase (PARP) or poly(ADP-ribose)synthase (PARS) hasan essential role in facilitating DNA repair, controlling RNAtranscription, mediating cell death, and regulating immune response.These actions make PARP inhibitors targets for a broad spectrum ofdisorders. PARP inhibitors have demonstrated efficacy in numerous modelsof disease, particularly in models of ischemia reperfusion injury,inflammatory disease, degenerative diseases, protection from adverseeffects of cytoxic compounds, and the potentiation of cytotoxic cancertherapy. PARP has also been indicated in retroviral infection and thusinhibitors may have use in antiretroviral therapy. PARP inhibitors havebeen efficacious in preventing ischemia reperfusion injury in models ofmyocardial infarction, stroke, other neural trauma, organtransplantation, as well as reperfusion of the eye, kidney, gut andskeletal muscle. Inhibitors have been efficacious in inflammatorydiseases such as arthritis, gout, inflammatory bowel disease, CNSinflammation such as MS and allergic encephalitis, sepsis, septic shock,hemmorhagic shock, pulmonary fibrosis, and uveitis. PARP inhibitors havealso shown benefit in several models of degenerative disease includingdiabetes (as well as complications) and Parkinsons disease. PARPinhibitors can ameliorate the liver toxicity following acetominophenoverdose, cardiac and kidney toxicities from doxorubicin and platinumbased antineoplastic agents, as well as skin damage secondary to sulfurmustards. In various cancer models, PARP inhibitors have been shown topotentiate radiation and chemotherapy by increasing cell death of cancercells, limiting tumor growth, decreasing metastasis, and prolonging thesurvival of tumor-bearing animals.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides compounds of Formula(I)

or a pharmaceutically acceptable salt thereof, wherein

R₁, R₂, R₃ and R₄ are independently selected from the group consistingof hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano,haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro,NR_(A)R_(B), and (NR_(A)R_(B))carbonyl;

X is aryl, arylalkyl, alkyl, heteroaryl, heteroarylalkyl,heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl,hydroxyalkyl, cycloalkyl, cycloalkylalkyl, NR_(C)R_(D),(NR_(C)R_(D))carbonyl, (NR_(C)R_(D))alkyl, (NR_(C)R_(D))carbonylalkyl,or -alkyl-CO₂G₁; wherein if X is aryl, arylalkyl, heteroaryl,heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,heterocyclecarbonyl, cycloalkyl, or cycloalkylalkyl then X may beunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z,independently selected from the group consisting of alkyl, alkenyl,alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl,alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, arylalkylcarbonyl,carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy,cycloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl,heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocyclecarbonylalkyl,hydroxy, hydroxyalkyl, NR_(C)R_(D), (NR_(C)R_(D))alkyl,(NR_(C)R_(D))carbonyl, (NR_(C)R_(D))carbonylalkyl, and oxo; wherein thearyl and the heteroaryl moieties of Z are independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of alkyl, formyl, halogen, and haloalkyl, and the heterocycleand cycloalkyl moieties of Z are independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of alkyl, oxo, formyl, halogen, and haloalkyl;

G₁ is hydrogen, alkyl, alkenyl, haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, orheterocyclealkyl; wherein the aryl, the aryl moiety of arylalkyl, theheteroaryl, the heteroaryl moiety of heteroarylakyl, the cycloalkyl, thecycloalkyl moiety of cycloalkylalkyl, the heterocycle, and theheterocycle moiety of heterocyclealkyl are independently unsubstitutedor substituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN,halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl,alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl,hydroxy, hydroxyalkyl, NR_(A)R_(B), (NR_(A)R_(B))alkyl,(NR_(A)R_(B))carbonyl, (NR_(A)R_(B))carbonylalkyl, and oxo;

R_(C) and R_(D) are independently selected from the group consisting ofhydrogen, alkyl, alkylcarbonyl, alkylcarbonyloxyalkylcarbonyl,arylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, carboxyalkyl,carboxyalkylcarbonyl, cycloalkyl, cycloalkylalkyl, haloalkyl,haloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl,heterocycle, heterocyclealkyl, heterocyclecarbonyl,heterocyclealkylcarbonyl, (NR_(A)R_(B))alkyl, and(NR_(A)R_(B))alkylcarbonyl; wherein if R_(C) or R_(D) are aryl,arylalkyl, arylalkylcarbonyl, arylcarbonyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle,heterocyclealkyl, heterocyclecarbonyl, or heterocyclealkylcarbonyl, thenR_(C) or R_(D) may be unsubstituted or substituted with 1, 2, 3, 4, or 5substituents independently selected from the group consisting of alkyl,alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, oxo, alkoxy,alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkylcarbonyl, andarylalkoxycarbonyl;

R_(A) and R_(B) are independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, and alkylcarbonyl; and

n is 1.

DETAILED DESCRIPTION OF THE INVENTION

In another embodiment, the present invention provides compounds ofFormula (I)

or a pharmaceutically acceptable salt thereof, wherein

R₁, R₂, R₃ and R₄ are hydrogen;

X is aryl, arylalkyl, alkyl, heteroaryl, heteroarylcarbonyl,heterocycle, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl,cycloalkyl, (NR_(C)R_(D))carbonyl, or (NR_(C)R_(D))alkyl; wherein if Xis aryl, arylalkyl, heteroaryl, heterocycle, heterocyclealkyl,heterocyclecarbonyl, or cycloalkyl, then X may be unsubstituted orsubstituted with 1 or 2 substituents, Z, independently selected from thegroup consisting of alkyl, nitro, —CN, halogen, alkoxy, alkoxycarbonyl,aryl, arylalkyl, arylalkoxycarbonyl, carboxy, cycloalkylalkyl,heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl,heterocyclealkylcarbonyl, NR_(C)R_(D), (NR_(C)R_(D))alkyl,(NR_(C)R_(D))carbonyl, and oxo; wherein the aryl and the heteroarylmoieties of Z are independently unsubstituted or substituted with 1, 2,3, 4, or 5 substituents selected from the group consisting of alkyl,formyl, halogen, and haloalkyl, and the heterocycle and cycloalkylmoieties of Z are independently unsubstituted or substituted with 1, 2,3, 4, or 5 substituents selected from the group consisting of alkyl,oxo, formyl, halogen, and haloalkyl;

R_(C) and R_(D) are independently selected from the group consisting ofhydrogen, alkyl, alkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, aryl,arylalkyl, arylalkylcarbonyl, arylcarbonyl, carboxyalkyl,carboxyalkylcarbonyl, cycloalkyl, haloalkyl, haloalkylcarbonyl,heteroaryl, heteroarylcarbonyl, heterocyclealkyl, heterocyclecarbonyl,heterocyclealkylcarbonyl, (NR_(A)R_(B))alkyl, and(NR_(A)R_(B))alkylcarbonyl; wherein if R_(C) or R_(D) arearylalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclealkyl,heterocyclecarbonyl, or heterocyclealkylcarbonyl, then R_(C) or R_(D)may be unsubstituted or substituted with one substituent selected fromthe group consisting of alkoxy, alkylcarbonyl and arylalkoxycarbonyl;

R_(A) and R_(B) are independently selected from the group consisting ofhydrogen, alkyl, and alkylcarbonyl; and

n is 1.

In another embodiment the present invention provide compounds of Formula(I) where X is selected from the group consisting of aryl, heteroaryl,heterocycle, and cycloalkyl.

In another embodiment, the present invention provides compounds ofFormula (II)

or a therapeutically acceptable salt thereof, wherein

R₁, R₂, R₃ and R₄ are independently selected from the group consistingof hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano,haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro,NR_(A)R_(B), and (NR_(A)R_(B))carbonyl;

X is aryl, arylalkyl, alkyl, heteroaryl, heteroarylalkyl,heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl,hydroxyalkyl, cycloalkyl, cycloalkylalkyl, NR_(C)R_(D),(NR_(C)R_(D))carbonyl, (NR_(C)R_(D))alkyl, (NR_(C)R_(D))carbonylalkyl,or -alkyl-CO₂G₁; wherein if X is aryl, arylalkyl, heteroaryl,heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,heterocyclecarbonyl, cycloalkyl, or cycloalkylalkyl then X may beunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z,independently selected from the group consisting of alkyl, alkenyl,alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl,alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, arylalkylcarbonyl,carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy,cycloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl,heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocyclecarbonylalkyl,hydroxy, hydroxyalkyl, NR_(C)R_(D), (NR_(C)R_(D))alkyl,(NR_(C)R_(D))carbonyl, (NR_(C)R_(D))carbonylalkyl, and oxo;

wherein the aryl and the heteroaryl moieties of Z are independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of alkyl, formyl, halogen, and haloalkyl, andthe heterocycle and cycloalkyl moieties of Z are independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of alkyl, oxo, formyl, halogen, and haloalkyl;

G₁ is hydrogen, alkyl, alkenyl, haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, orheterocyclealkyl; wherein the aryl, the aryl moiety of arylalkyl, theheteroaryl, the heteroaryl moiety of heteroarylakyl, the cycloalkyl, thecycloalkyl moiety of cycloalkylalkyl, the heterocycle, and theheterocycle moiety of heterocyclealkyl are independently unsubstitutedor substituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN,halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl,alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl,hydroxy, hydroxyalkyl, NR_(A)R_(B), (NR_(A)R_(B))alkyl,(NR_(A)R_(B))carbonyl, (NR_(A)R_(B))carbonylalkyl, and oxo;

R_(C) and R_(D) are independently selected from the group consisting ofhydrogen, alkyl, alkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, aryl,arylalkyl, arylalkylcarbonyl, arylcarbonyl, carboxyalkyl,carboxyalkylcarbonyl, cycloalkyl, cycloalkylalkyl, haloalkyl,haloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl,heterocycle, heterocyclealkyl, heterocyclecarbonyl,heterocyclealkylcarbonyl, (NR_(A)R_(B))alkyl, and(NR_(A)R_(B))alkylcarbonyl; wherein if R_(C) or R_(D) are aryl,arylalkyl, arylalkylcarbonyl, arylcarbonyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle,heterocyclealkyl, heterocyclecarbonyl, or heterocyclealkylcarbonyl, thenR_(C) or R_(D) may be unsubstituted or substituted with 1, 2, 3, 4, or 5substituents independently selected from the group consisting of alkyl,alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, oxo, alkoxy,alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkylcarbonyl, andarylalkoxycarbonyl; and

R_(A) and R_(B) are independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, and alkylcarbonyl.

In another embodiment, the present invention provides compounds ofFormula (III)

or a pharmaceutically acceptable salt thereof, wherein

R₁, R₂, R₃ and R₄ are independently selected from the group consistingof hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano,haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro,NR_(A)R_(B), and (NR_(A)R_(B))carbonyl;

X is aryl, arylalkyl, alkyl, heteroaryl, heteroarylalkyl,heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl,hydroxyalkyl, cycloalkyl, cycloalkylalkyl, NR_(C)R_(D),(NR_(C)R_(D))carbonyl, (NR_(C)R_(D))alkyl, (NR_(C)R_(D))carbonylalkyl,or -alkyl-CO₂G₁; wherein if X is aryl, arylalkyl, heteroaryl,heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,heterocyclecarbonyl, cycloalkyl, or cycloalkylalkyl then X may beunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z,independently selected from the group consisting of alkyl, alkenyl,alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl,alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, arylalkylcarbonyl,carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy,cycloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl,heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocyclecarbonylalkyl,hydroxy, hydroxyalkyl, NR_(C)R_(D), (NR_(C)R_(D))alkyl,(NR_(C)R_(D))carbonyl, (NR_(C)R_(D))carbonylalkyl, and oxo; wherein thearyl and the heteroaryl moieties of Z are independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of alkyl, formyl, halogen, and haloalkyl, and the heterocycleand cycloalkyl moieties of Z are independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of alkyl, oxo, formyl, halogen, and haloalkyl;

G₁ is hydrogen, alkyl, alkenyl, haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, orheterocyclealkyl; wherein the aryl, the aryl moiety of arylalkyl, theheteroaryl, the heteroaryl moiety of heteroarylakyl, the cycloalkyl, thecycloalkyl moiety of cycloalkylalkyl, the heterocycle, and theheterocycle moiety of heterocyclealkyl are independently unsubstitutedor substituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, nitro, —CN,halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl,alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl,hydroxy, hydroxyalkyl, NR_(A)R_(B), (NR_(A)R_(B))alkyl,(NR_(A)R_(B))carbonyl, (NR_(A)R_(B))carbonylalkyl, and oxo;

R_(C) and R_(D) are independently selected from the group consisting ofhydrogen, alkyl, alkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, aryl,arylalkyl, arylalkylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl,cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkylcarbonyl, heteroaryl,heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,heterocyclecarbonyl, heterocyclealkylcarbonyl, (NR_(A)R_(B))alkyl, and(NR_(A)R_(B))alkylcarbonyl; wherein if R_(C) or R_(D) are aryl,arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heteroaryl,heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,heterocyclecarbonyl, or heterocyclealkylcarbonyl, then R_(C) or R_(D)may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, nitro, —CN, halogen, haloalkyl, oxo, alkoxy, alkylcarbonyl,alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryl, arylalkyl, arylalkoxy, arylalkylcarbonyl, and arylalkoxycarbonyl;and

R_(A) and R_(B) are independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, and alkylcarbonyl.

In another embodiment, the present invention provides compounds ofFormula (II) wherein X is aryl or arylalkyl wherein the aryl orarylalkyl may be unsubstituted or substituted with 1, 2, 3, 4, or 5substituents, Z, independently selected from the group consisting ofalkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy,alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl,arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylalkyl,heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle,heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl,heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR_(C)R_(D),(NR_(C)R_(D))alkyl, (NR_(C)R_(D))carbonyl, and(NR_(C)R_(D))carbonylalkyl; wherein the aryl and the heteroaryl moietiesof Z are independently unsubstituted or substituted with 1, 2, 3, 4, or5 substituents selected from the group consisting of alkyl, formyl,halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties of Zare independently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, oxo, formyl,halogen, and haloalkyl.

In another embodiment, the present invention provides compounds ofFormula (II) wherein X is heteroaryl which may be unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents, Z, independentlyselected from the group consisting of alkyl, alkenyl, alkynyl, nitro,—CN, halogen, haloalkyl, alkoxy, alkylcarbonyl, alkylcarbonylalkyl,alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryl, arylalkyl,arylalkoxy, arylalkoxycarbonyl, arylalkylcarbonyl, carboxy,carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy,cycloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl,heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocyclecarbonylalkyl,hydroxy, hydroxyalkyl, NR_(C)R_(D), (NR_(C)R_(D))alkyl,(NR_(C)R_(D))carbonyl, and (NR_(C)R_(D))carbonylalkyl; wherein the aryland the heteroaryl moieties of Z are independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of alkyl, formyl, halogen, and haloalkyl, and the heterocycleand cycloalkyl moieties of Z are independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of alkyl, oxo, formyl, halogen, and haloalkyl.

In another embodiment, the present invention provides compounds ofFormula (II) wherein X is heterocycle or heterocyclealkyl wherein theheterocycle or heterocyclealkyl may be unsubstituted or substituted with1, 2, 3, 4, or 5 substituents, Z, independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl,alkoxy, alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl,arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylalkyl,heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle,heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl,heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR_(C)R_(D),(NR_(C)R_(D))alkyl, (NR_(C)R_(D))carbonyl, (NR_(C)R_(D))carbonylalkyl,and oxo; wherein the aryl and the heteroaryl moieties of Z areindependently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, formyl,halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties of Zare independently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, oxo, formyl,halogen, and haloalkyl.

In another embodiment, the present invention provides compounds ofFormula (III) wherein X is heteroarylcarbonyl, heterocyclealkyl,heterocyclecarbonyl, hydroxyalkyl, (NR_(C)R_(D))carbonyl,(NR_(C)R_(D))alkyl, or aryl wherein if X is heteroarylcarbonyl,heterocyclealkyl, heterocyclecarbonyl, or aryl, then X may beunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, Z,independently selected from the group consisting of alkyl, alkenyl,alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl,alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, arylalkylcarbonyl,carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy,cycloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl,heteroarylcarbonylalkyl, heterocycle, heterocyclealkyl,heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocyclecarbonylalkyl,hydroxy, hydroxyalkyl, NR_(C)R_(D), (NR_(C)R_(D))alkyl,(NR_(C)R_(D))carbonyl, (NR_(C)R_(D))carbonylalkyl, and oxo; wherein thearyl and the heteroaryl moieties of Z are independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of alkyl, formyl, halogen, and haloalkyl, and the heterocycleand cycloalkyl moieties of Z are independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of alkyl, oxo, formyl, halogen, and haloalkyl.

In another embodiment, the present invention provides compounds ofFormula (I) wherein R₁, R₂, R₃ and R₄ are hydrogen.

In another embodiment, the present invention provides compounds ofFormula (II) wherein R₁, R₂, R₃ and R₄ are hydrogen.

In another embodiment, the present invention provides compounds ofFormula (III) wherein R₁, R₂, R₃ and R₄ are hydrogen. In anotherembodiment, the present invention provides compounds selected from thegroup consisting of

3-phenyl-4H-pyrazolo[1,5-a]quinazolin-5-one;

3-(4-chloro-phenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-phenyl-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-tert-butyl-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-furan-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-thiophen-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(4-methoxyphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(3-nitrophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(3-chlorophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-biphenyl-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-biphenyl-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(3-aminophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(2-chlorophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-[3-(2-aminoethylamino)phenyl]-4H-pyrazolo[1,5-a]quinazolin-5-one;

N-{2-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenylamino]ethyl}-acetamide;

N-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]acetamide;

benzyl4-({acetyl[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]amino}methyl)piperidine-1-carboxylate;

2-[3-(2-dimethylaminoethylamino)phenyl]-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-piperidin-3-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-methylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-ethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-isobutylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-cyclopropylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-[1-(3-piperidin-1-ylpropionyl)piperidin-3-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-propylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-benzylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-cyclopentylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-pyridin-4-ylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-isopropylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

methyl 4-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)benzoate;

2-(3-fluoro-4-morpholin-4-ylphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-cyclopropyl-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-benzylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

N-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]-3-piperidin-1-ylpropionamide;

2-piperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(4-pyrrolidin-1-ylmethylphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-methylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-ethylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-propylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-cyclopropylmethylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-isobutylpiperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-isopropylpiperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-pyrrolidin-3-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;

benzyl3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)pyrrolidine-1-carboxylate;

2-(1-methylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-ethylpylrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-cyclopropylmethylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-piperidin-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-methylpiperidin-2-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

(S)-2-acetylamino-4-methyl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)pentanamide;

(R)-2-methoxy-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-2-phenylacetamide;

N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)isonicotinamide;

N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-3-piperidin-1-yl-propionamide;

N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-3-pylrolidin-1-yl-propionamide;

2-morpholin-4-yl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)acetamide;

3-morpholin-4-yl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-propionamide;

2-phenethyl-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-benzyl-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-piperidin-4-ylmethyl-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(1-methylpiperidin-4-ylmethyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;

2-(3-bromobenzyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;

3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzonitrile;

2-[3-(aminomethyl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one;

2-(3-pyridin-3-ylbenzyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;

2-[3-(2-oxopyrrolidin-1-yl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one;

3′-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]-1,1′-biphenyl-2-carbaldehyde;

2-[3-(2-fluoropyridin-4-yl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one;

methyl3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzoate;

3-[(4-methylpiperazin-1-yl)carbonyl]pyrazolo[1,5-a]quinazolin-5(4H)-one;

3-(pyrrolidin-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;

N,N-dimethyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;

3-(piperidin-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;

N-cyclopropyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;

5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;

N-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;

N-ethyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;

N-benzyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;

5-oxo-N-(2-phenylethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;

3-(azepan-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;

3-(morpholin-4-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;

3-(piperazin-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;

N-cyclohexyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;

3-(1H-imidazol-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;

5-oxo-N-(piperidin-4-ylmethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;

3-{[3-(aminomethyl)piperidin-1-yl]carbonyl}pyrazolo[1,5-a]quinazolin-5(4H)-one;

5-oxo-N-phenyl-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;

4-{[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)carbonyl]amino}butanoicacid;

3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzoic acid;

5-oxo-N-(2-piperidin-1-ylethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;

3-(Hydroxymethyl)pyrazolo[1,5-a]quinazolin -5-(4H)-one;

3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzamide;

3-(aminomethyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;

N-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]glycine;

4-chloro-N-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]butanamide;

4-oxo-4-{[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]amino}butanoicacid;

1-acetyl-N-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]piperidine-4-carboxamide;

2-oxo-2-{[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]amino}ethylacetate;

3-(pyrrolidin-1-ylmethyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;

1-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]pyrrolidine-2,5-dione;and

N-((5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl)acetamide; Inanother embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, in combination with a therapeuticallyacceptable carrier.

In another embodiment, the present invention provides a method ofinhibiting PARP in a mammal in recognized need of such treatmentcomprising administering to the mammal a therapeutically acceptableamount of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention provides a method oftreating cancer in a mammal in recognized need of such treatmentcomprising administering to the mammal a therapeutically acceptableamount of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention provides a method fordecreasing tumor volume in a mammal in recognized need of such treatmentcomprising administering to the mammal a therapeutically acceptableamount of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention provides a method oftreating leukemia, colon cancer, glioblastomas, lymphomas, melanomas,carcinomas of the breast, or cervical carcinomas in a mammal inrecognized need of such treatment comprising administering to the mammala therapeutically acceptable amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method ofpotentiation of cytotoxic cancer therapy in a mammal in recognized needof such treatment comprising administering to the mammal atherapeutically acceptable amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method ofpotentiation of radiation therapy in a mammal in recognized need of suchtreatment comprising administering to the mammal a therapeuticallyacceptable amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the present invention provides a method oftreating ischemia reperfusion injury associated with, but not limitedto, myocardial infarction, stroke, other neural trauma, and organtransplantation, in a mammal in recognized need of such treatmentcomprising administering to the mammal a therapeutically acceptableamount of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention provides a method ofreperfusion including, but not limited to, reperfusion of the eye,kidney, gut and skeletal muscle, in a mammal in recognized need of suchtreatment comprising administering to the mammal a therapeuticallyacceptable amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the present invention provides a method oftreating inflammatory diseases including, but not limited to, arthritis,gout, inflammatory bowel disease, CNS inflammation, multiple sclerosis,allergic encephalitis, sepsis, septic shock, hemmorhagic shock,pulmonary fibrosis, and uveitis in a mammal in recognized need of suchtreatment comprising administering to the mammal a therapeuticallyacceptable amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the present invention provides a method oftreating immunological diseases or disorders such as rheumatoidarthritis and septic shock in a mammal in recognized need of suchtreatment comprising administering to the mammal a therapeuticallyacceptable amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the present invention provides a method oftreating degenerative disease including, but not limited to, diabetesand Parkinsons disease, in a mammal in recognized need of such treatmentcomprising administering to the mammal a therapeutically acceptableamount of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention provides a method oftreating hypoglycemia in a mammal in recognized need of such treatmentcomprising administering to the mammal a therapeutically acceptableamount of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention provides a method oftreating retroviral infection in a mammal in recognized need of suchtreatment comprising administering to the mammal a therapeuticallyacceptable amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the present invention provides a method oftreating liver toxicity following acetominophen overdose in a mammal inrecognized need of such treatment comprising administering to the mammala therapeutically acceptable amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method oftreating cardiac and kidney toxicities from doxorubicin and platinumbased antineoplastic agents in a mammal in recognized need of suchtreatment comprising administering to the mammal a therapeuticallyacceptable amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the present invention provides a method oftreating skin damage secondary to sulfur mustards in a mammal inrecognized need of such treatment comprising administering to the mammala therapeutically acceptable amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to prepare a medicament for inhibiting the PARP enzyme in a mammal inrecognized need of such treatment.

In another embodiment, the present invention provides a use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to prepare a medicament for inhibiting tumor growth in a mammal inrecognized need of such treatment.

In another embodiment, the present invention provides a use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to prepare a medicament for treating cancer in a mammal in recognizedneed of such treatment.

In another embodiment, the present invention provides a use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to prepare a medicament for treating leukemia, colon cancer,glioblastomas, lymphomas, melanomas, carcinomas of the breast, orcervical carcinomas in a mammal in a mammal in recognized need of suchtreatment.

In another embodiment, the present invention provides a use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to prepare a medicament for potentiation of cytotoxic cancer therapy ina mammal in recognized need of such treatment comprising administeringto the mammal a therapeutically acceptable amount of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to prepare a medicament for potentiation of radiation in a mammal inrecognized need of such treatment comprising administering to the mammala therapeutically acceptable amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to prepare a medicament for treating ischemia reperfusion injuryassociated with, but not limited to, myocardial infarction, stroke,other neural trauma, and organ transplantation, in a mammal inrecognized need of such treatment comprising administering to the mammala therapeutically acceptable amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to prepare a medicament for treating reperfusion including, but notlimited to, reperfusion of the eye, kidney, gut and skeletal muscle, ina mammal in recognized need of such treatment comprising administeringto the mammal a therapeutically acceptable amount of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to prepare a medicament for treating inflammatory diseases including,but not limited to, arthritis, gout, inflammatory bowel disease, CNSinflammation, multiple sclerosis, allergic encephalitis, sepsis, septicshock, hemmorhagic shock, pulmonary fibrosis, and uveitis in a mammal inrecognized need of such treatment comprising administering to the mammala therapeutically acceptable amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to prepare a medicament for treating immunological diseases or disorderssuch as rheumatoid arthritis and septic shock in a mammal in recognizedneed of such treatment comprising administering to the mammal atherapeutically acceptable amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to prepare a medicament for treating degenerative disease including, butnot limited to, diabetes and Parkinsons disease, in a mammal inrecognized need of such treatment comprising administering to the mammala therapeutically acceptable amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to prepare a medicament for treating hypoglycemia in a mammal inrecognized need of such treatment comprising administering to the mammala therapeutically acceptable amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to prepare a medicament for treating retroviral infection in a mammal inrecognized need of such treatment comprising administering to the mammala therapeutically acceptable amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to prepare a medicament for treating liver toxicity followingacetaminophen overdose in a mammal in recognized need of such treatmentcomprising administering to the mammal a therapeutically acceptableamount of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention provides a use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to prepare a medicament for treating cardiac and kidney toxicities fromdoxorubicin and platinum based antineoplastic agents in a mammal inrecognized need of such treatment comprising administering to the mammala therapeutically acceptable amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to prepare a medicament for treating skin damage secondary to sulfurmustards in a mammal in recognized need of such treatment comprisingadministering to the mammal a therapeutically acceptable amount of acompound of Formula (I) or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides pharmaceuticalcompositions comprising a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof, in combination with a therapeuticallyacceptable carrier.

Definitions

As used throughout this specification and the appended claims, thefollowing terms have the following meanings:

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkyl” as used herein, means at least one alkoxy group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples of alkoxyalkylinclude, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl,2-methoxyethyl, and methoxymethyl.

The term “alkoxycarbonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxycarbonylalkyl” as used herein, means an alkoxycarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein.

The term “alkyl” as used herein, means a saturated, straight or branchedchain hydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkylcarbonylalkyl” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough a alkyl group, as defined herein.

The term “alkylcarbonyloxy” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen atom. Representative examples of alkylcarbonyloxyinclude, but are not limited to, acetyloxy, ethylcarbonyloxy, andtert-butylcarbonyloxy.

The term “alkylcarbonyloxyalkyl” as used herein, means analkylcarbonyloxy group, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.

The term “alkylcarbonyloxyalkylcarbonyl” as used herein, means analkylcarbonyloxyalkyl group, as defined herein, appended to the parentmolecular moiety through a carbonyl group.

The term “alkylenyl” as used herein, means a divalent group derived froma saturated, straight or branched chain hydrocarbon of from 1 to 6carbon atoms. Representative examples include, but are not limited to,—CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂CH(CH₃)CH₂—.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “aryl,” as used herein, means a phenyl group or a naphthylgroup.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of arylalkyl include, but arenot limited to, benzyl, 2-phenylethyl, 3-phenylpropyl,1-methyl-3-phenylpropyl, and 2-naphth-2-ylethyl.

The term “arylalkoxy” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkoxy group,as defined herein.

The term “arylalkoxycarbonyl” as used herein, means an arylalkoxy group,as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein.

The term “arylalkylcarbonyl” as used herein, means an arylalkyl group,as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. The alkyl of arylalkylcarbonyl groupsof the present invention may be substituted with an alkoxy substituent.

The term “arylcarbonyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through a carbonylgroup, as defined herein The term “carbonyl” as used herein, means a—C(O)— group.

The term “carboxy” as used herein, means a —CO₂H group.

The term “cyano” as used herein, means a —CN group.

The term “carboxyalkyl” as used herein, means a carboxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein.

The term “carboxyalkylcarbonyl” as used herein, means a carboxyalkylgroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein.

The term “cycloalkyl” as used herein, means a saturated cyclichydrocarbon group containing from 3 to 8 carbons, examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl.

The term “cycloalkylalkoxy” as used herein, means a cycloalkyl group, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein.

The term “cycloalkylalkyl” as used herein, means a cycloalkyl group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of cycloalkylalkylinclude, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl,cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.

The term “cycloalkylcarbonyl” as used herein, means a cycloalkyl group,as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein.

The term “formyl” as used herein, means a —C(O)H group.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkyl” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, 3-chloropropyl, chloromethyl, 2-fluoroethyl,trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “haloalkoxy” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, chloromethoxy, 2-fluoroethoxy,trifluoromethoxy, and pentafluoroethoxy.

The term “haloalkylcarbonyl” as used herein, means a haloalkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein.

The term “heteroaryl,” as used herein, means a monocyclic heteroarylring or a bicyclic heteroaryl ring. The monocyclic heteroaryl ring is a5 or 6 membered ring. The 5 membered ring has two double bonds andcontains one, two, three or four heteroatoms independently selected fromthe group consisting of N, O, and S. The 6 membered ring has threedouble bonds and contains one, two, three or four heteroatomsindependently selected from the group consisting of N, O, and S. Thebicyclic heteroaryl ring consists of the 5 or 6 membered heteroaryl ringfused to a phenyl group or the 5 or 6 membered heteroaryl ring is fusedto another 5 or 6 membered heteroaryl ring. Nitrogen heteroatomscontained within the heteroaryl may be optionally oxidized to theN-oxide. The heteroaryl is connected to the parent molecular moietythrough any carbon atom contained within the heteroaryl whilemaintaining proper valence. Representative examples of heteroarylinclude, but are not limited to, benzothienyl, beizoxadiazolyl,cinnolinyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolyl,isoxazolyl, isoquinolinyl, isothiazolyl, naplithyridinyl, oxadiazolyl,oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl,pyrrolyl, pyridinium N-oxide, quinolinyl, tetrazolyl, thiadiazolyl,thiazolyl, thienopyridinyl, thienyl, triazolyl, and triazinyl.

The term “heteroarylalkyl” as used herein, means a heteroaryl, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of heteroarylalkylinclude, but are not limited to, pyridinymethyl.

The term “heteroarylcarbonyl” as used herein, means a heteroaryl, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein.

The term “heteroarylcarbonylalkyl” as used herein, means aheteroarylcarbonyl, as defined herein, appended to the parent molecularmoiety through an alkyl group, as defined herein.

The term “heterocycle” or “heterocyclic” as used herein, means amonocyclic or bicyclic heterocyclic ring. The monocyclic heterocyclicring consists of a 3, 4, 5, 6, 7, or 8 membered ring containing at leastone heteroatom independently selected from O, N, and S. The 3 or 4membered ring contains 1 heteroatom selected from the group consistingof O, N and S. The 5 membered ring contains zero or one double bond andone, two or three heteroatoms selected from the group consisting of 0, Nand S. The 6 or 7 membered ring contains zero, one or two double bondsand one, two or three heteroatoms selected from the group consisting ofO , N and S. The bicyclic heterocyclic ring consists of a monocyclicheterocyclic ring fused to a cycloalkyl group or the monocyclicheterocyclic ring fused to a phenyl group or the monocyclic heterocyclicring fused to another monocyclic heterocyclic ring. The heterocycle isconnected to the parent molecular moiety through any carbon or nitrogenatom contained within the heterocycle while maintaining proper valence.Representative examples of heterocycle include, but are not limited to,azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl,1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl,imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl,oxazolidinyl, piperazinyl, piperidinyl, pyrazolinyl, pyrazolidinyl,pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl,thiazolidinyl, thiomolpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, and trithianyl.

The term “heterocyclealkyl” as used herein, means a heterocycle, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein.

The term “heterocyclealkylcarbonyl” as used herein, means aheterocyclealkyl, as defined herein, appended to the parent molecularmoiety through a carbonyl group, as defined herein.

The term “heterocyclecarbonyl” as used herein, means a heterocycle, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein.

The term “heterocyclecarbonylalkyl” as used herein, means aheterocyclecarbonyl, as defined herein, appended to the parent molecularmoiety through an alkyl group, as defined herein.

The term “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, means at least one hydroxygroup, as defined herein, is appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “nitro” as used herein, means a —NO₂ group.

The term “NR_(A)R_(B)” as used herein, means two groups, R_(A) and R_(B), which are appended to the parent molecular moiety through a nitrogenatom.

The term “(NR_(A)R_(B))alkyl” as used herein, means a NR_(A)R_(B)group,as defined herein, appended to the parent molecular moiety through analkyl group.

The term “(NR_(A)R_(B))carbonyl” as used herein, means aNR_(A)R_(B)group, as defined herein, appended to the parent molecularmoiety through a carbonyl group, as defined herein. Representativeexamples of (NR_(A)R_(B))carbonyl include, but are not limited to,aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

The term “(NR_(A)R_(B))carbonylalkyl” as used herein, means a(NR_(A)R_(B))carbonyl group, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.

The term “(NR_(A)R_(B))alkylcarbonyl” as used herein, means a(NR_(A)R_(B))alkyl group, as defined herein, appended to the parentmolecular moiety through a carbonyl group, as defined herein.

The term “NR_(C)R_(D)” as used herein, means two groups, R_(C) andR_(D), which are appended to the parent molecular moiety through anitrogen atom.

The term “(NR_(C)R_(D))alkyl” as used herein, means a NR_(C)R_(D)group,as defined herein, appended to the parent molecular moiety through analkyl group.

The term “(NR_(C)R_(D))carbonyl” as used herein, means aNR_(C)R_(D)group, as defined herein, appended to the parent molecularmoiety through a carbonyl group, as defined herein. Representativeexamples of (NR_(C)R_(D))carbonyl include, but are not limited to,aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

The term “(NR_(C)R_(D))carbonylalkyl” as used herein, means a(NR_(C)R_(D))carbonyl group, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.

The term “oxo” as used herein, means a ═O moiety.

Compounds of the present invention can exist as stereoisomers, whereinasymmetric or chiral centers are present. Stereoisomers are designated(R) or (S) depending on the configuration of substituents around thechiral carbon atom. The terms (R) and (S) used herein are configurationsas defined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., (1976), 45: 13-30, herebyincorporated by reference. The present invention contemplates variousstereoisomers and mixtures thereof and are specifically included withinthe scope of this invention. Stereoisomers include enantiomers,diastereomers, and mixtures of enantiomers or diastereomers. Individualstereoisomers of compounds of the present invention may be preparedsynthetically from commercially available starting materials whichcontain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution well-known to those of ordinary skill inthe art. These methods of resolution are exemplified by (1) attachmentof a mixture of enantiomers to a chiral auxiliary, separation of theresulting mixture of diastereomers by recrystallization orchromatography and liberation of the optically pure product from theauxiliary or (2) direct separation of the mixture of optical enantiomerson chiral chromatographic columns.

Compounds of the present invention were named by ACD/ChemSketch version5.06 (developed by Advanced Chemistry Development, Inc., Toronto, ON,Canada) or were given names which appeared to be consistent with ACDnomenclature.

Determination of Biological Activity

Inhibition of PARP

Nicotinamide[2,5′,8-3H]adenine dinucleotide and strepavidin SPA beadswere purchased from Amersham Biosiences (UK) Recombinant HumanPoly(ADP-Ribose) Polymerase (PARP) purified from E.coli and6-Biotin-17-NAD⁺, were purchase from Trevigen, Gaithersburg, MD. NAD⁺,Histone, aminobenzamide, 3-amino benzamide and Calf Thymus DNA (dcDNA)were purchased from Sigma, St. Louis, Mo. Stem loop oligonucleotidecontaining MCAT sequence was obtained from Qiagen. The oligos weredissoloved to 1 mM in annealing buffer containing 10 mM Tris HCl pH 7.5,1 mM EDTA, and 50 mM NaCl, incubated for 5min at 95° C., and followed byannealing at 45° C. for 45 minutes. Histone H1 (95% electrophoreticallypure) was purchased from Roche, Indianapolis, Ind. Biotinylated histoneH1 was prepared by treating the protein with Sulfo-NHS-LC-Biotin fromPierce Rockford, Ill. The biotinylation reaction was conducted by slowlyand intermittently adding 3 equivalents of 10 mM Sulfo-NHS-LC-Biotin to100 μM Histone H1 in phosphate-buffered saline, pH 7.5, at 4° C. withgentle vortexing over 1 min followed by subsequent 4° C. incubation for1 hr. Streptavidin coated (FlashPlate Plus) microplates were purchasedfrom Perkin Elmer, Boston, Mass.

PARP1 assay was conducted in PARP assay buffer containing 50 mM Tris pH8.0, 1 mM DTT, 4 mM MgCl₂. PARP reactions contained 1.5 μM [³H]-NAD⁺(1.6 uCi/mmol), 200 nM biotinylated histone H1, 200 nM s1DNA, and 1 nMPARP enzyme. Auto reactions utilizing SPA bead-based detection werecarried out in 100 μl volumes in white 96 well plates. Reactions wereinitiated by adding 50 μl of 2× NAD⁺ substrate mixture to 50 μl of 2×enzyme mixture containing PARP and DNA. These reactions were terminatedby the addition of 150 μl of 1.5 mM benzamide (˜1000-fold over itsIC50). 170 μl of the stopped reaction mixtures were transferred tostreptavidin Flash Plates, incubated for 1 hr, and counted using aTopCount microplate scintillation counter. The K_(i) data was determinedfrom inhibition curves at various substrate concentrations and are shownin Table 1 for compounds of the present invention TABLE 1 Inhibition ofPARP (nM) 44 69 846 364 520 >9500 266 178 40 142 299 390 920 550 350 774277 46 1700 256 831 211 >9500 35 6400 419 327 1000 214 1337 413 271 53668 621 920 321 775 >9500 >9500 >9500 >9500 >9500 >9500 >95009390 >9500 >9500 >9500 >9500 7960 >9500 >9500 >9500 >9500 >9500 >9500 55146 255 213 114 1230 92 86 1880 31 164Cellular PARP Assay:

C41 cells were treated with a compound of the present invention for 30minutes in 96 well plate. PARP was then activated by damaging DNA with 1mM H₂O₂ for 10 minutes. The cells were then washed with ice-cold PBSonce and fixed with pre-chilled methanol:acetone (7:3) at −20° C. for 10minutes. After air-drying, the plates were rehydrated with PBS andblocked 5% non-fat dry milk in PBS-tween (0.05%) (blocking solution) for30 minutes at room temperature. The cells were incubated with anti-PARantibody 10H (1:50) in Blocking solution at 37° C. for 60 minutesfollowed by washing with PBS-Tween20 5 times, and incubation with goatanti-mouse fluorescein 5(6)-isothiocyanate-coupled antibody (1:50) and 1μg/ml 4′,6-diamidino-2-phenylindole (DAPI) in blocking solution at 37°C. for 60 minutes. After washing with PBS-Tween20 5 times, the analysiswas performed using an finax Fluorescence Microplate Reader (MolecularDevices, Sunnyvalle, Calif.), set at the excitation wavelength of 490 nmand emission wavelength of 528 nm fluorescein 5(6)-isothiocyanate (FITC)or the excitation wavelength of 355 nm and emission wavelength of 460 nm(DAPI). The PARP activity (FITC signal) was normalized with cell numbers(DAPI).

The cellular assay measures the formation of poly ADP-ribose by PARPwithin cells and demonstrates that compounds of the present inventionpenetrate cell membranes and inhibit PARP in intact cells. The EC_(50s)for representative compounds of the present invention are provided inTable 2. TABLE 2 Cellular Activity EC₅₀ (nM) 16 9.6 1.1 >1000 24 >1000106

As PARP inhibitors, the compounds of the present invention have numeroustherapeutic applications related to, ischemia reperfusion injury,inflammatory diseases, degenerative diseases, protection from adverseeffects of cytotoxic compounds, and potentiation of cytotoxic cancertherapy. In particular, compounds of the present invention potentiateradiation and chemotherapy by increasing cell death of cancer cells,limiting tumor growth, decreasing metastasis, and prolonging thesurvival of tumor-bearing mammals. Compounds of Formula (I) can treatleukemia, colon cancer, glioblastomas, lymphomas, melanomas, carcinomasof the breast, and cervical carcinomas.

Other therapeutic applications include, but are not limited to,retroviral infection, arthritis, gout, inflammatory bowel disease, CNSinflammation, multiple sclerosis, allergic encephalitis, sepsis, septicshock, hemmorhagic shock, pulmonary fibrosis, uveitis, diabetes,Parkinsons disease, myocardial infarction, stroke, other neural trauma,organ transplantation, reperfusion of the eye, reperfusion of thekidney, reperfusion of the gut, reperfusion of skeletal muscle, livertoxicity following acetominophen overdose, cardiac and kidney toxicitiesfrom doxorubicin and platinum based antineoplastic agents, and skindamage secondary to sulfur mustards. (G. Chen et al. Cancer Chemo.Pharmacol. 22 (1988), 303; C. Thiemermann et al., Proc. Natl. Acad. Sci.USA 94 (1997), 679-683 D. Weltin et al. Int. J. Immunopharmacol. 17(1995), 265-271; H. Kröger et al. Inflammation 20 (1996), 203-215; W.Elirlich et al. Rheumatol. Int. 15 (1995), 171-172; C. Szabo et al.,Proc. Natl. Acad. Sci. USA 95 (1998), 3867-3872; S. Cuzzocrea et al.Eur. J. Pharmacol. 342 (1998), 67-76; V. Burkhart et al., NatureMedicine (1999), 5314-19).

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the present invention can be employedas a zwitterion or as a pharmaceutically acceptable salt. By a“therapeutically effective amount” of the compound of the invention ismeant a sufficient amount of the compound to treat or prevent a diseaseor disorder ameliorated by a PARP inhibitor at a reasonable benefit/riskratio applicable to any medical treatment. It will be understood,however, that the total daily usage of the compounds and compositions ofthe present invention will be decided by the attending physician withinthe scope of sound medical judgment. The specific therapeuticallyeffective dose level for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder; activity of the specific compound employed; thespecific composition employed, the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors well known in themedical arts. For example, it is well within the skill of the art tostart doses of the compound at levels lower than those required toachieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved.

By “pharmaceutically acceptable salt” is meant those salts which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell-known in the art. The salts can be prepared in situ during thefinal isolation and purification of the compounds of the presentinvention or separately by reacting the free base of a compound of thepresent invention with a suitable acid. Representative acids include,but are not limited to acetatic, citric, aspartic, benzoic,benzenesulfonic, butyric, fumaric, hydrochloric, hydrobromic,hydroiodic, lactic, maleic, methanesulfonic, pamoic, pectinic, pivalic,propionic, succinic, tartaric, phosphic, glutamic, andp-toluenesulfonic. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides such as methyl,ethyl, propyl, and butyl chlorides, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chainhalides such as decyl, lauryl, myristyl and stearyl chlorides, bromidesand iodides; arylalkyl halides like benzyl and phenethyl bromides andothers. Water or oil-soluble or dispersible products are therebyobtained.

A compound of the present invention may be administered as apharmaceutical composition containing a compound of the presentinvention in combination with one or more pharmaceutically acceptableexcipients. A pharmaceutically acceptable carrier or excipient refers toa non-toxic solid, semi-solid or liquid filler, diluent, encapsulatingmaterial or formulation auxiliary of any type. The compositions can beadministered parenterally, intracisternally, intravaginally,intraperitoneally, topically (as by powders, ointments, drops ortransdermal patch), rectally, or bucally. The term “parenteral” as usedherein refers to modes of administration which include intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous andintraarticular injection and infusion.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically-acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, as well as sterile powders forreconstitution into sterile injectable solutions or dispersions justprior to use. Examples of suitable aqueous and nonaqueous carriers,diluents, solvents or vehicles include water, ethanol, polyols (such asglycerol, propylene glycol, polyethylene glycol, and the like),carboxymethylcellulose and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity may be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions can also contain adjuvants such as preservative,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents which delay absorption,such as aluminum monostearate and gelatin.

Compounds of the present invention may also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals that are dispersed inan aqueous medium. Any non-toxic, physiologically-acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andthe phosphatidyl cholines (lecithins), both natural and synthetic.Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Total daily dose of the compositions of the invention to be administeredto a human or other mammal host in single or divided doses may be inamounts, for example, from 0.0001 to 300 mg/kg body weight daily andmore usually 1 to 300 mg/kg body weight. The dose, from 0.0001 to 300mg/kg body, may be given twice a day.

Abbreviations which have been used in the descriptions of the examplesthat follow are: CDI for carbonyl diimidazole; DBU for1,8-diazabicyclo[5.4.0]undec-7-ene; DME for 1,2-dimethoxyethane; DMF forN,N-dimethylforamide; DMSO for dimethylsulfoxide; Et₂O for diethylether; EtOAc for ethyl acetate; EtOH for ethanol; HPLC for high pressureliquid chromatography; LDA for lithium diisopropylamide; MeOH formethanol; psi for pounds per square inch; it for room temperature; TFAfor trifluoroacetic acid; THF for tetrahydrofuran, and TMS fortrimethylsilane.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes whichtogether illustrate the methods by which the compounds of the inventionmay be prepared. The synthesis of compounds of formula (I) wherein thegroups R₁, R₂, R₃, R₄, X, R_(A) and R_(B) are as set forth in thesummary of the invention unless otherwise noted, is exemplified inSchemes 1-4.

Optimum reaction conditions and reaction times for each individual stepmay vary depending on the particular reactants employed and substituentspresent in the reactants used. Unless otherwise specified, solvents,temperatures and other reaction conditions may be readily selected byone of ordinary skill in the art. Specific procedures are provided inthe Synthetic Examples section. Reactions may be worked up in theconvention manner, e.g. by eliminating the solvent from the residue andfurther purified according to methodologies generally known in the artsuch as, but are not limited to, crystallization, distillation,extraction, trituration and chromatography. Unless otherwise described,the starting materials and reagents are either commercially available ormay be prepared by one skilled in the art from commercially availablematerials using methods described in the chemical literature.

This invention is intended to encompass compounds having formula (I)when prepared by synthetic processes or by metabolic processes.Preparation of the compounds of the invention by metabolic processesinclude those occurring in the human or animal body (in vivo) orprocesses occurring in vitro.

Routine experimentation, including appropriate manipulation of thereaction conditions, reagents used and sequence of the synthetic route,protection of any chemical functionality that may not be compatible withthe reaction conditions, and deprotection at suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well know to those skilled in the art; examples of which maybe found in T. Greene and P. Wuts, Protecting Groups in ChemicalSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999), which isincorporated herein by reference in its entirety. Synthesis of thecompounds of formula (I) may be accomplished by methods analogous tothose described in the following schemes and in specific examples.

Compounds of formula (I) wherein X is represented by R′ and R″ and oneof R′ and R″ is hydrogen, can be prepared using the general procedure asillustrated in scheme 1.

Compound of formula (6) can be obtained by (a) deprotonation of nitrile(3) with a base such as, but not limited to, n-butyl lithium and the (b)contacting the anion obtained from step (a) with an acid chloride (2) oran ester (1) wherein R¹⁰¹ is C₁₋₆ alkyl, to provide compound (4).Alternatively, the anion obtained from step (a) can be treated with (1)wherein R¹⁰¹ is hydrogen, in the presence of a coupling reagent such as,but not limited to, N,N′-carbonyldiimidazole or1,3-dicyclohexylcarbodiimide to provide compound (4). Treatment of2-hydrazinobenzoic acid (5) and compound (4) in a acetic acid, in amicrowave reactor and at elevated temperature (for example, 150° C.)generates 4H-pyrazolo[1,5-a]quinazolin-5-one (6) wherein one of R′ andR″ is hydrogen and the other is X (as defined in formula (I)).

Compounds having general formula (I) wherein X is NR_(C)R_(D)alkyl,R_(C) is hydrogen or alkyl, and R_(D) is alkyl, alkylcarbonyl,heteroarylcarbonyl, heterocyclealkylcarbonyl orNR_(A)R_(B)alkylcarbonyl, can be prepared as shown in Scheme 2.

A 3-cyano-4H-pyrazolo[1,5-a]quinazolin-5-one (7), prepared using theconditions as described in Scheme 1, or purchased, can be reduced to the3-aminomethyl analog (8) using an appropriate reducing agent such asammonia in methanol and Raney nickel, under about 60 psi of hydrogengas. Coupling of (8) with a carboxylic acid of formula R₁₀₂COOH whereinR₁₀₂ is alkyl, heteroaryl, heterocyclealkyl or NR_(A)R_(B)alkyl, in thepresence of a coupling reagent such as, but not limited to,1,3-dicyclohexylcarbodiimide, a coupling auxiliary such as, but notlimited to, 1-hydroxybenzotriazole hydrate, and a base such as, but notlimited to diisopropylethyl amine, provides compound of formula (9). Thereaction is generally performed in a solvent such as, but not limitedto, N,N-dimethylacetamide, at ambient temperature or with heating (forexample, at about 100-150° C.) and optionally in a microwave reactor.Compound (8) can also be coupled with an acid chloride R₁₀₂COC1 in thepresence of a base such as pyridine and in a solvent such as DMF, oralternatively, (8) can be coupled with an anhydride (R₁₀₂CO)₂O in thepresence of a base such as diisopropylethylamine and in a solvent suchas methanol. Compound (8) can also be alkylated with an halide offormula R₁₀₃X wherein R₁₀₃ is alkyl, aralkyl, heteroarylalkyl,heterocyclealkyl or NR_(A)R_(B)alkyl, in the presence of a base such assodium ethoxide or can be reacted with an aldehyde R₁₀₄CHO or ketoneR₁₀₄R₁₀₅C(O) wherein R₁₀₄ and R₁₀₅ are alkyl, aryl, aralkyl, heteroaryl,heteroarylalkyl, heterocyclealkyl or NR_(A)R_(B)alkyl, under reductiveamination conditions, such as sodium cyanoborohydride in methanol, togive the N-alkyl analog (10).

Compounds having general formula (I) wherein X is aryl, heteroaryl,heteroarylalkyl, or aralkyl, can be prepared as shown in Scheme 3.

A bromo 2- or 3-aryl, heteroaryl, heteroarylalkyl, oraralkyl-4H-pyrazolo[1,5-a]quinazolin-5-one of formula (11), where A isaryl, heteroaryl, heteroarylalkyl, is prepared using the conditions asdescribed in Scheme 1. This compound can be carbonylated under palladiumcatalysis in the presence of methanol or other alcohols to give themethyl ester (12). Saponification using, for example, sodium hydroxidein ethanol, gave the acid (13). Acid (13) can be converted to amide (14)using an amine NHR_(C)R_(D) under standard peptide coupling conditionssuch as 1,3-dicyclohexylcarbodiimide or 1,1′-carbonyldiimidazole.Bromide (11) can also be coupled with an aryl or heteroaryl boronic acidor an aryl or heteroaryl trialkylstannane under palladium catalysisconditions to provide compounds of formula (15), where Ar is aryl orheteroaryl. In addition, bromide (11) can be converted to nitrile (16)using zinc cyanide under palladium catalysis conditions. Nitrile (16)can be reduced to amine (17) using, for example, Raney nickel andhydrogen. Amines of formula (17) can be further functionalized to amides(18) wherein R₁₀₂ is alkyl, arylalkyl, heterocycle, heterocyclealkyl, orNR_(A)R_(B)alkyl, and substituted amines (19) as described for thepreparation of (9) and (10) in Scheme 2.

Compounds having general formula (I) wherein X is NR_(C)R_(D)carbonyl,R_(C) and R_(D) are hydrogen, alkyl, aryl, heteroaryl, heterocycle,heterocyclealkyl or (NR_(A)R_(B))alkyl, can be prepared as shown inScheme 4.

A 2- or 3-carboalkoxy-4H-pyrazolo[1,5-a]quinazolin-5-one (20), isprepared using the conditions as described in Scheme 1. This compoundcan be saponified to the corresponding carboxylic acid (21) understandard acidic (ie, hydrochloric acid) or basic (ie, sodium hydroxide)conditions. Reduction using a reducing agent such as lithium aluminumhydride in tetrahydrofuran provided the alcohol (22). This can beconverted to ether (23) wherein R₁₀₂ is alkyl, heteroaryl,heterocyclealkyl or (NR_(A)R_(B))alkyl, under standard Williamson ethersynthesis conditions with an alkyl halide or under standard Mitsunobuconditions. Alternately, acid (21) can be converted to amide (24) usingan amine NHR_(C)R_(D) under standard peptide coupling conditions such as1,3-dicyclohexylcarbodiimide or 1,1′-carbonyldiimidazole.

The following Examples are intended as an illustration of and not alimitation upon the scope of the invention as defined in the appendedclaims. The compounds of this invention can be prepared by a variety ofsynthetic routes.

EXAMPLE 1 3-phenyl-4H-pyrazolo[1,5-a]quinazolin-5-one

A mixture of 2-hydrazinobenzoic acid (0.15 g, 0.8 mmol) and3-oxo-2-phenyl-propionitrile (0.116 g, 0.8 mmol) in acetic acid (0.2 mL)was heated in a microwave (Personal Chemistry SmithSynthesizer) at 150°C. for 10 minutes. The precipitated product was filtered, washed withmethanol and diethyl ether and dried. ¹H NMR (DMSO-d₆) δ 12.10 (s, 1H),8.10-8.19 (m, 3H) 7.88-7.96 (m, 1H), 7.59 (d, J=7.3 Hz, 2H), 7.52 (t,J=7.8 Hz, 1H), 7.42 (t, J=7.6 Hz, 2Hz), 7.28 (t, J=7.3 Hz, 1H).

EXAMPLE 2 3-(4-chloro-phenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 1, substituting2-(4-chlorophenyl)-3-oxo-propionitrile for 3-oxo-2-phenylpropionitrile.¹H NMR (DMSO-d₆) δ 12.14 (s, 1H), 8.12-8.19 (m, 2H) 7.89-7.94 (m, 1H),7.62 (d, J=7.7 Hz, 2H), 7.53 (t, J=7.5 Hz, 1H), 7.44-7.48 (m, 2H).

EXAMPLE 3 2-phenyl-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 1, substituting3-oxo-3-phenylpropionitrile for 3-oxo-2-phenylpropionitrile. ¹H NMR(DMSO-d₆) δ 12.30 (s, 1H), 8.15-8.18 (m, 2H) 7.97 (d, J=7.1 Hz, 2H),7.91 (t, J=7.8 Hz, 1H), 7.45-7.53 (m, 3H), 7.40 (t, J=7.2 Hz, 1H), 6.38(s, 1H).

EXAMPLE 4 2-tert-butyl-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 1, substituting4,4-dimethyl-3-oxo-pentanenitrile for 3-oxo-2-phenylpropionitrile. ¹HNMR (DMSO-d₆) δ 12.09 (s, 1H), 8.11 (dd, J=8.0, 1.2 Hz, 1H) 8.02 (d,J=7.7 Hz, 2H), 7.82-7.87 (m, 1H), 7.41-7.46 (m, 1H), 5.80 (s, 1H), 1.32(s, 9H).

EXAMPLE 5 2-furan-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 1, substituting3-furan-2-yl-3-oxopropionitrile for 3-oxo-2-phenylpropionitrile. ¹H NMR(DMSO-d₆) δ 12.28 (s, 1H), 8.08-8.17 (m, 2H), 7.90 (td, J=7.8, 1.5 Hz,1H), 7.80 (d, J=1.8 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 6.99 (d, J=3.4 Hz,1H), 6.64 (dd, J=3.4, 1.8 Hz, 1H), 6.19 (s, 1H).

EXAMPLE 6 2-thiophen-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 1, substituting3-oxo-3-thiophen-2-yl-propionitrile for 3-oxo-2-phenylpropionitrile. ¹HNMR (DMSO-d₆) δ 12.30 (s, 1H), 8.15 (d, J=8.0 Hz, 1H) 8.08 (d, J=7.7 Hz,1H), 7.90 (td, J=7.8, 1.5 Hz, 1H), 7.58-7.65 (m, 2H), 7.47-7.53 (m, 1H),7.15 (dd, J=5.1, 3.5 Hz, 1H), 6.30 (s, 1H).

EXAMPLE 7 2-(4-methoxyphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 1, substituting3-(4-methoxyphenyl)-3-oxo-propionitrile for 3-oxo-2-phenylpropionitrile.¹H NMR (DMSO-d₆) δ 12.25 (s, 1H), 8.12-8.17 (m, 2H), 7.87-7.92 (m, 3H),7.46-7.51 (m, 1H), 7.03 (d, J=8.9 Hz, 2H), 6.30 (s, 1H), 3.82 (s, 3H).

EXAMPLE 8 2-(3-nitrophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 1, substituting3-(3-nitrophenyl)-3-oxo-propionitrile for 3-oxo-2-phenylpropionitrile.¹H NMR (DMSO-d₆) δ 12.40 (s, 1H), 8.74-8.76 (m, 1H), 8.42 (dd, J=6.4,1.5 Hz, 1H), 8.16-8.26 (m, 3H), 7.90-7.95 (m, 1H), 7.78 (t, J=8.0 Hz,1H), 7.52-7.56 (m, 1H), 6.59 (s, 1H).

EXAMPLE 9 2-(3-chlorophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 1, substituting3-(3-chlorophenyl)-3-oxo-propionitrile for 3-oxo-2-phenylpropionitrile.¹H NMR (DMSO-d₆) δ 12.37 (s, 1H), 8.19 (d, J=7.9 Hz, 1H), 8.16 (dd,J=7.9, 1.2 Hz, 1H), 8.04 (t, J=1.8 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H),7.87-7.94 (m, 1H), 7.45-7.54 (m, 3H), 6.49 (s, 1H).

EXAMPLE 10 2-biphenyl-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 1, substituting3-biphenyl-2-yl-3-oxo-propionitrile for 3-oxo-2-phenylpropionitrile. ¹HNMR (DMSO-d₆) δ 11.94 (s, 1H), 8.11 (dd, J=7.9, 1.2 Hz, 1H), 8.05 (d,J=8.2 Hz, 1H), 7.85-7.92 (m, 2H), 7.46-7.53 (m, 3H), 7.33-7.41 (m, 4H),7.28 (dd, J=7.8, 1.7 Hz, 2H), 5.19 (s, 1H).

EXAMPLE 11 2-biphenyl-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 1, substituting3-biphenyl-4-yl-3-oxo-propionitrile for 3-oxo-2-phenylpropionitrile. ¹HNMR (DMSO-d₆) δ 12.29 (s, 1H), 8.14-8.20 (m, 2H), 7.92 (td, J=7.3, 2.1Hz, 2H), 7.57-7.63 (m, 1H), 7.53 (t, J=7.0 Hz, 1H), 7.44-7.50 (m, 2H),6.39 (s, 1H).

EXAMPLE 12 2-(3-am inophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one

A mixture of EXAMPLE 8 (1.07 g, 3.5 mmol) and 10% palladium on carbon(0.2 g) in methanol (25 mL) was stirred overnight under 1 atmosphere ofhydrogen and filtered. The filtrate was concentrated and the residuecrystallized from methanol to provide the title compound (0.58 g, 60%).¹H NMR (DMSO-d₆) δ 12.23 (s, 1H), 8.10-8.18 (m, 2H), 7.86-7.95 (m, 1H),7.49 (t, J=7.0 Hz, 1H), 7.19 (s, 1H), 7.05-7.12 (m, 2H), 6.56-6.63 (m,1H), 6.20 (s, 1H), 5.19 (s, 2H).

EXAMPLE 13 2-(2-chlorophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 1, substituting3-(2-chlorophenyl)-3-oxo-propionitrile for 3-oxo-2-phenylpropionitrile.¹H NMR (DMSO-d₆) δ 12.34 (s, 1H), 8.15-8.21 (m, 2H), 8.07 (d, J=8.2 Hz,2H), 7.90-7.95 (m, 1H), 7.73-7.81 (m, 4H), 7.51 (q, J=7.7 Hz, 3H), 7.40(t, J=7.3 Hz, 1H), 6.44 (s, 1H).

EXAMPLE 142-[3-(2-aminoethylamino)phenyl]-4H-pyrazolo[1,5-a]quinazolin-5-one

A solution of EXAMPLE 12 (0.06 g, 0.2 mmol) and tert-butyl(2-oxoethyl)carbamate (0.035 g, 0.2 mmol) in ethanol (1 mL) andacetonitrile (1 mL) was treated with sodium cyanoborohydride (0.014 g,0.2 mmol) and acetic acid (0.2 mL). The mixture was heated in amicrowave at 170° C. for 40 minutes and concentrated. The residue waspurified by flash chromatography on silica gel with 10%methanol/dichloromethane/0.1% ammonium hydroxide to provide the titlecompound. ¹H NMR (DMSO-d₆) δ 12.30 (s, 1H), 10.06 (s, 1H), 8.11-8.19 (m,2H), 7.89-7.96 (m, 1H), 7.58-7.67 (m, 2H), 7.52 (t, J=7.6 Hz, 1H), 7.39(t, J=7.9 Hz, 1H), 6.27 (s, 1H), 3.30-3.36 (m, 4H), 2.08 (s, 3H).

EXAMPLE 15N-{2-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenylamino]ethyl}-acetamide

The title compound was obtained as a byproduct in the purification ofEXAMPLE 14. ¹H NMR (DMSO-d₆) δ 12.25 (s, 1H), 8.12-8.18 (m, 2H), 7.91(td, J=7.8, 1.5 Hz, 2H), 7.47-7.53 (m, 1H), 7.13-7.20 (m, 2H), 6.60-6.68(m, 1H), 6.27 (s, 1H), 3.22-3.26 (m, 2H), 3.14-3.19 (m, 2H), 1.76 (s,3H).

EXAMPLE 16N-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]acetamide

A solution of EXAMPLE 12 (0.04 g, 0.1 mmol) and acetic anhydride (0.02mL, 1.5 mmol) in acetonitrile was treated with triethylamine (0.1 mL,0.8 mmol). The mixture was stirred overnight at ambient temperature andfiltered to provide the title compound. ¹H NMR (DMSO-d₆) δ 12.27 (s,1H), 10.04 (s, 1H), 8.11-8.20 (m, 3H), 7.87-7.95 (m, 1H), 7.58-7.66 (m,2H), 7.48-7.56 (m, 1H), 7.38 (t, J=7.8 Hz, 1H), 6.27 (s, 1H), 2.06-2.12(m, 3H).

EXAMPLE 17 benzyl 4-({acetyl[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]amino}methyl)piperidine-1-carboxylate

The title compound was prepared as described in EXAMPLE 14, substitutingbenzyl 4-formylpiperidine-1-carboxylate for tert-butyl(2-oxoethyl)carbamate. ¹H NMR (DMSO-d₆) δ 8.15-8.20 (m, 2H), 7.88-7.98(m, 3H), 7.49-7.57 (m, 2H), 7.30-7.38 (m, 6H), 6.49 (s, 1H), 5.05 (s,2H), 3.94 (s, 2H), 3.64 (d, J=6.8 Hz, 2H), 3.37-3.42 (m, 1H), 3.35 (s,3H), 1.77-1.84 (m, 2H), 1.68 (d, J=12.0 Hz, 3H), 1.09 (t, J=6.9 Hz, 2H).

EXAMPLE 182-[3-(2-dimethylaminoethylamino)phenyl]-4H-pyrazolo[1,5-a]quinazolin-5-one

A solution of EXAMPLE 12 (0.04 g, 0.1 mmol) and (2-bromoethyl)dimethylamine (0.02 g, 0.1 mmol) in acetonitrile (1 mL) was treated withpotassium carbonate (0.04 g, 0.3 mmol). The mixture was stirredovernight at 50° C. and filtered. The filtrate was concentrated andpurified by flash chromatography on silica gel with 10%methanol/dichloromethane to provide the title compound. ¹H NMR (DMSO-d₆)δ 8.12-8.18 (m, 2H), 7.86-7.95 (m, 1H), 7.49 (t, J=7.6 Hz, 1H),7.12-7.20 (m, 3H), 6.64 (s, 1H), 6.27 (s, 1H), 3.23-3.26 (m, 3H),2.57-2.65 (m, 1H), 2.31 (s, 6H), 1.24 (s, 1H), 0.85 (s, 1H).

EXAMPLE 19 2-piperidin-3-yl-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 1, substitutingtert butyl 3-(2-cyanoacetyl)piperidine-1-carboxylate for3-oxo-2-phenylpropionitrile. ¹H NMR (DMSO-d₆) δ 12.23 (s, 1H), 8.85 (s,2H), 8.13 (d, J=8.0 Hz, 1H), 8.04 (d, J=7.7 Hz, 1H), 7.88 (td, J=7.8,1.53 Hz, 1H), 7.46-7.51 (m, 1H), 5.91 (s, 1H), 3.44-3.52 (m, 1H),3.27-3.33 (m, 2H), 3.09-3.21 (m, 2H), 2.92 (s, 1H), 2.04-2.11 (m, 1H),1.84-1.91 (m, 1H), 1.71-1.82 (m, 1H).

EXAMPLE 20

2-(1-methylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one

A solution of EXAMPLE 19 (0.04 g, 0.1 mmol) and formaldehyde (36% inwater, 0.018 mL, 2 mmol) in methanol (1 mL) was treated with sodiumcyanoborohydride (0.009 g, 0.1 mmol) and acetic acid (0.1 mL). Themixture was stirred overnight at ambient temperature and concentrated.The residue was purified by HPLC on a C18 column with 0-100%acetonitrile/water/0.1% trifluoroacetic acid to provide the titlecompound as the trifluoroacetate salt. ¹H NMR (CD₃OD) δ 8.23 (d, J=7.1Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.84-7.89 (m, 1H), 7.46-7.52 (m, 1H),5.95 (s, 1H), 3.63-3.74 (m, 1H), 3.35-3.48 (m, 3H), 3.05-3.17 (m, 1H),2.94 (s, 3H), 2.15-2.24 (m, 1H), 2.01-2.08 (m, 1H), 1.84-1.95 (m, 2H).

EXAMPLE 21 2-(1-ethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as the trifluoroacetate salt asdescribed in EXAMPLE 20, substituting acetaldehyde for formaldehyde. ¹HNMR (CD₃OD) δ 8.23 (dd, J=8.0, 1.5 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.87(td, J=7.8, 1.2 Hz, 1H), 7.47-7.51 (m, 1H), 5.96 (s, 1H), 3.65 (s, 1H),3.49 (d, J=7.1 Hz, 1H), 3.19 (dd, J=7.2, 2.3 Hz, 3H), 3.01 (s, 1H), 2.19(s, 1H), 2.03 (s, 1H), 1.85-1.97 (m, 2H), 1.40 (t, J=7.4 Hz, 3H).

EXAMPLE 222-(1-isobutylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as the trifluoroacetate salt asdescribed in EXAMPLE 20, substituting 2-methylpropionaldehyde forformaldehyde. ¹H NMR (DMSO-d₆) δ 12.26 (s, 1H), 8.12-8.19 (m, 1H), 8.02(d, J=7.6 Hz, 1H), 7.86-7.92 (m, 1H), 7.49 (t, J=7.6 Hz, 1H), 5.90 (s,1H), 3.66 (s, 1H), 3.37-3.47 (m, 9H), 3.17 (d, J=4.9 Hz, 1H), 2.82 (s,3H), 2.07 (s, 1H), 1.91 (s, 1H), 1.79 (s, 1H), 1.60 (s, 1H).

EXAMPLE 232-(1-cyclopropylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as the trifluoroacetate salt asdescribed in EXAMPLE 20, substituting cyclopropanecarbaldehyde forformaldehyde. ¹H NMR (CD₃OD) δ 8.23 (dd, J=8.0, 1.5 Hz, 1H), 8.14 (d,J=8.3 Hz, 1H), 7.86 (td, J=7.8, 1.5 Hz, 1H), 7.46-7.51 (m, 1H), 5.95 (s,1H), 3.74 (s, 1H), 3.32-3.42 (m, 3H), 3.07 (d, J=7.4 Hz, 3H), 2.20 (d,J=7.4 Hz, 1H), 2.05 (s, 1H), 1.85-1.97 (m, 2H), 1.14-1.24 (m, 1H),0.74-0.84 (m, 2H), 0.41-0.50 (m, 2H).

EXAMPLE 242-[1-(3-piperidin-1-ylpropionyl)piperidin-3-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one

A solution of EXAMPLE 19 (0.1 g, 0.4 mmol), 3-piperidin-1-ylpropionicacid (0.06 g, 0.4 mmol), 1-hydroxybenzotriazole (0.098 g, 0.7 mmol),benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(0.377 g, 0.7 mmol) and diisopropylethylamine (0.4 mL, 2.2 mmol) inN,N′-dimethylformamide (4 mL) was heated in a microwave at 150° C. for10 minutes. The mixture was concentrated and purified by HPLC on a C18column with 0-100% acetonitrile/water/0.1% trifluoroacetic acid toprovide the title compound as the trifluoroacetate salt. ¹H NMR (CD₃OD)δ 8.20-8.26 (m, 1H), 8.11 (dd, J=8.3, 4.6 Hz, 1H), 7.83-7.89 (m, 1H),7.44-7.50 (m, 1H), 5.92 (d, J=11.0 Hz, 1H), 4.65-4.79 (m, 1H), 4.08-4.14(m, 1H), 4.01-4.05 (m, 1H), 3.48-3.59 (m, 5H), 3.35-3.42 (m, 2H),2.92-3.04 (m, 5H), 2.16-2.23 (m, 1H), 1.84-1.95 (m, 4H), 1.73-1.82 (m,2H), 1.49-1.60 (m, 1H).

EXAMPLE 25 2-(1-propylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 20, substitutingpropionaldehyde for formaldehyde. The crude product was purified byflash chromatography on silica gel with 0-10%methanol/dichloromethane/0.1% ammonium hydroxide. ¹H NMR (CD₃OD) δ 8.23(d, J=8.0, Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.87 (t, J=7.4 Hz, 1H), 7.49(t, J=7.7 Hz, 1H), 5.96 (s, 1H), 3.47-3.57 (m, 1H), 3.34-3.43 (m, 1H),3.14 (t, J=8.1 Hz, 4H), 2.14-2.26 (m, 1H), 1.83-1.94 (m, 4H), 1.14-1.24(m, 1H), 1.07 (t, J=7.2 Hz, 4H).

EXAMPLE 26 2-(1-benzylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 20, substitutingbenzaldehyde for formaldehyde. HPLC purification was followed by flashchromatography on silica gel with 0-10% methanol/dichloromethane/0.1%ammonium hydroxide. ¹H NMR (CD₃OD) δ 8.21 (dd, J=8.0, 1.5 Hz, 1H), 8.06(d, J=8.3 Hz, 1H), 7.82-7.88 (m, 1H), 7.35-7.46 (m, 6H), 5.87 (s, 1H),3.84-3.93 (m, 2H), 3.09-3.18 (m, 2H), 2.67 (s, 1H), 2.48-2.57 (m, 1H),2.07-2.14 (m, 1H), 1.79-1.91 (m, 2H), 1.68 (s, 1H).

EXAMPLE 272-(1-cyclopentylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 20, substitutingcyclopentanecarboxaldehyde for formaldehyde. HPLC purification wasfollowed by flash chromatography on silica gel with 0-10%methanol/dichloromethane/0.1% ammonium hydroxide. ¹H NMR (CD₃OD) δ 8.21(d, J=8.0, Hz, 1H), 8.11 (d, J=7.7 Hz, 1H), 7.82-7.87 (m, 1H), 7.45 (t,J=8.1 Hz, 1H), 5.88 (s, 1H), 3.19-3.25 (m, 1H), 3.01-3.11 (m, 2H), 2.47(d, J=7.1 Hz, 2H), 2.32 (s, 1H), 2.17 (dt, J=15.1, 7.6 Hz, 2H), 2.07(dd, J=13.0, 3.8 Hz, 1H), 1.78-1.87 (m, 4H), 1.61-1.70 (m, 2H),1.52-1.61 (m, 3H), 1.19-1.29 (m, 2H).

EXAMPLE 282-(1-pyridin-4-ylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 20, substitutingpyridine-4-carboxaldehyde for formaldehyde. HPLC purification wasfollowed by flash chromatography on silica gel with 0-10%methanol/dichloromethane/0.1% ammonium hydroxide. ¹H NMR (CD₃OD) δ8.45-8.50 (m, 2H), 8.20 (dd, J=8.0, 1.5 Hz, 1H), 8.08 (d, J=7.3 Hz, 1H),7.78-7.86 (m, 1H), 7.42-7.48(m, 3H), 5.86 (s, 1H), 3.64 (s, 1H), 3.49(q, J=7.06 Hz, 1H), 3.01-3.10 (m, 2H), 2.87 (s, 1H), 2.24-2.31 (m, 1H),2.17 (td, J=11.1, 3.5 Hz, 1H), 2.05 (s, 1H), 1.74-1.86 (m, 2H), 1.58 (d,J=12.6 Hz, 1H).

EXAMPLE 292-(1-isopropylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one

A solution of EXAMPLE 19 (0.07 g, 0.3 mmol) and 2-iodopropane (0.09 mL,0.9 mmol) in dioxane (2 mL) and was treated with sodium hydride (0.01 g,0.4 mmol). The mixture was stirred overnight at 65° C., cooled toambient temperature, treated with water and concentrated. The residuewas purified by flash chromatography on silica gel with 10%methanol/dichloromethane to provide the title compound. ¹H NMR (CD₃OD) δ8.21 (dd, J=8.0, 1.5 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.81-7.87 (m, 1H),7.42-7.47 (m, 1H), 5.88 (s, 1H), 3.21 (dt, J=11.3, 1.9, 1H), 2.99-3.10(m, 2H), 2.92 (dt, J=13.2, 6.6 Hz, 1H), 2.51 (t, J=11.0 Hz, 1H), 2.38(td, J=11.5, 2.8 Hz, 1H), 2.09 (ddd, J=9.0, 3.8, 3.7 Hz, 1H), 1.83-1.92(m, 1H), 1.70-1.82 (m, 1H), 1.59 (qd, J=12.3, 4.0 Hz, 1H), 1.14-1.19 (m,6H).

EXAMPLE 30 methyl4-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)benzoate

The title compound was prepared as described in EXAMPLE 1, substitutingmethyl 4-(2-cyanoacetyl) benzoate for 3-oxo-2-phenylpropionitrile. ¹HNMR (DMSO-d₆) δ 12.37 (s, 1H), 8.11-8.21 (m, 4H) 8.04-8.08 (m, 2H),7.89-7.98 (m, 1H), 7.53 (t, J=7.6 Hz, 1H), 6.50 (s, 1H), 3.89 (s, 3H).

EXAMPLE 312-(3-fluoro-4-morpholin-4-ylphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 1, substituting3-(3-fluoro-4-morpholin-4-ylphenyl)-3-oxo-propionitrile for3-oxo-2-phenylpropionitrile. ¹H NMR (DMSO-d₆) δ 12.30 (s, 1H), 8.15 (d,J=8.1 Hz, 2H), 7.86-7.95 (m, 1H), 7.69-7.78 (m, 2H), 7.49 (t, J=7.8 Hz,1H), 7.11 (t, J=8.6 Hz, 1H), 6.37 (s, 1H), 3.77 (s, 4H), 3.09 (d, J=4.1Hz, 4H).

EXAMPLE 32 2-cyclopropyl-4H-pyrazolo[1,5-a]quinazolin-5-one EXAMPLE 32A3-cyclopropyl-3-oxopropionitrile

A solution of acetonitrile (0.25 mL, 4.8 mmol) in tetrahydrofuran (3 mL)was cooled to −78° C. and treated with 1.6 M n-butyl lithium in hexanes(3 mL, 4.8 mmol). The mixture was stirred at −78° C. for 2 hours and asolution of cyclopropanecarbonyl chloride (0.22 mL, 2.4 mmol) intetrahydrofuran (1 mL) was added. The mixture was stirred for 1 hour and20% hydrochloric acid was added until the pH=3. The mixture was dilutedwith ethyl acetate, washed with water and brine, filtered through silicagel and concentrated to provide the title compound.

EXAMPLE 32B 2-cyclopropyl-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 1, substitutingEXAMPLE 32A for 3-oxo-2-phenylpropionitrile. ¹H NMR (DMSO-d₆) δ 12.07(s, 1H), 8.10 (dd, J=8.0, 1.5 Hz, 1H), 7.98 (d, J=7.7 Hz, 1H), 7.84 (td,J=7.8, 1.5 Hz, 1H), 7.39-7.47 (m, 1H), 5.62 (s, 1H), 1.95-2.03 (m, 1H),0.96 (ddd, J=8.3, 6.4, 4.0 Hz, 2H), 0.78 (ddd, J=7.0, 4.5, 4.1 Hz, 2H).

EXAMPLE 33 2-(1-benzylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-oneEXAMPLE 33A 3-(1-benzylpiperidin-4-yl)-3-oxo-propionitrile

The title compound was prepared as described in EXAMPLE 32A,substituting methyl 1-benzylpiperidin-4-carboxylate forcyclopropanecarbonyl chloride.

EXAMPLE 33B2-(1-benzylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 1, substitutingEXAMPLE 33A for 3-oxo-2-phenylpropionitrile. ¹H NMR (CD₃OD) δ 8.22 (d,J=7.8 Hz, 1H), 8.06 (s, 1H), 7.81-7.89 (m, 1H), 7.45-7.56 (m, 6H), 5.89(s, 1H), 4.36 (s, 2H), 3.51-3.65 (m, 2H), 3.13-3.29 (m, 2H), 2.25-2.29(m, 2H), 1.96-2.11 (m, 1H).

EXAMPLE 34 N-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]-3-piperidin-1-ylpropionamide

A solution of EXAMPLE 12 (0.1 g, 0.4 mmol), 3-piperidinopropionic acid(60 mg, 0.4 mmol), 1-hydroxybenzotriazole (0.098 g, 0.7 mmol),benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(0.377 g, 0.7 mmol) and diisopropylethylamine (0.4 mL, 2.2 mmol) inN,N′-dimethylformamide (4 mL) was heated in a microwave at 100° C. for15 minutes. The mixture was concentrated and purified by flashchromatography on silica gel with 10% methanol/dichloromethane toprovide the title compound. ¹H NMR (CD₃OD) δ 8.23-8.27 (m, 3H), 7.89(td, J=7.8, 1.5 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.59 (dd, J=7.1, 2.2Hz, 1H), 7.48-7.56 (m, 1H), 7.42 (t, J=8.0 Hz, 1H), 6.33 (s, 1H), 3.62(s, 2H), 3.51 (t, J=6.6 Hz, 2H), 3.04 (s, 2H), 2.96 (t, J=6.8 Hz, 2H),1.98 (d, J=3.4 Hz, 2H), 1.82 (s, 3H), 1.58 (s, 1H).

EXAMPLE 35 2-piperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one

A mixture of EXAMPLE 33 (0.15 g, 0.4 mmol) and 10% palladium on carbon(0.02 g) in methanol (5 mL) was stirred overnight under 1 atmospherehydrogen and filtered. The filtrate was concentrated and the residuepurified by flash chromatography on silica gel with 10%methanol/dichloromethane to provide the title compound. ¹H NMR (CD₃OD) δ8.22 (dd, J=7.9, 1.2 Hz, 1H), 8.11 (d, J=8.2 Hz, 1H), 7.83-7.88 (m, 1H),7.47 (t, J=7.6 Hz, 1H), 5.91 (s, 1H), 3.50 (dt, J=13.0, 3.7 Hz, 2H),3.12-3.19 (m, 2H), 2.29 (dd, J=15.0, 3.4 Hz, 2H), 1.99-2.08 (m, 2H).

EXAMPLE 362-(4-pyrrolidin-1-ylmethylphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 1, substituting3-oxo-3-(4-pyrrolidin-1-ylmethylphenyl)propionitrile for3-oxo-2-phenylpropionitrile. ¹H NMR (CD₃OD) δ 8.22-8.29 (m, 2H), 8.07(d, J=8.2 Hz, 2H), 7.89-7.93 (m, 1H), 7.62 (d, J=8.2 Hz, 2H), 7.52 (t,J=7.2 Hz, 1H), 6.40 (s, 1H), 4.43 (s, 2H), 3.50-3.57 (m, 2H), 3.19-3.27(m, 2H), 2.18-2.25 (m, 2H), 1.98-2.07 (m, 2H).

EXAMPLE 37 2-(1-methylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 20, substitutingEXAMPLE 35 for EXAMPLE 19. The crude product was purified by flashchromatography on silica gel with 0-10% methanol/dichloromethane/0.1%ammonium hydroxide. ¹H NMR (DMSO-d₆) δ 12.12 (s, 1H), 8.12 (d, J=7.1 Hz,1H), 8.01 (d, J=8.0 Hz, 1H), 7.83-7.87 (m, 1H), 7.43-7.47 (m, 1H), 5.79(s, 1H), 2.98-3.07 (m, 2H), 2.67-2.77 (m, 1H), 2.38 (s, 5H), 1.95-2.02(m, 2H), 1.72-1.83 (m, 2H).

EXAMPLE 38 2-(1-ethylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 21, substitutingEXAMPLE 35 for EXAMPLE 19. The crude product was purified by flashchromatography on silica gel with 0-10% methanol/dichloromethane/0.1%ammonium hydroxide. ¹H NMR (DMSO-d₆) δ 12.18 (s, 1H), 8.13 (d, J=7.1 Hz,1H), 8.01 (d, J=8.6 Hz, 1H), 7.87 (td, J=7.8, 1.5 Hz, 1H), 7.44-7.49 (m,1H), 5.81 (s, 1H), 3.51 (s, 2H), 3.17 (d, J=5.2 Hz, 1H), 3.08 (s, 2H),2.99 (s, 2H), 2.16 (s, 2H), 2.02 (s, 2H) 1.27 (s, 3H).

EXAMPLE 39 2-(1-propylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 25, substitutingEXAMPLE 35 for EXAMPLE 19. ¹H NMR (DMSO-d₆) δ 8.12 (dd, J=7.8, 1.4 Hz,1H), 8.01 (d, J=8.0 Hz, 1H), 7.84-7.88 (m, 1H), 7.44-7.48 (m, 1H), 5.81(s, 1H), 3.15 (s, 1H), 2.85-2.90 (m, 4H), 2.04-2.13 (m, 2H), 1.88-1.99(m, 3H), 1.65 (s, 2H), 0.91 (t, J=7.5 Hz, 4H).

EXAMPLE 402-(1-cyclopropylmethylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 23, substitutingEXAMPLE 35 for EXAMPLE 19. The crude product was purified by flashchromatography on silica gel with 0-10% methanol/dichloromethane/0.1%ammonium hydroxide. ¹H NMR (DMSO-d₆) δ 12.18 (s, 1H), 8.11-8.14 (m, 1H),8.01 (d, J=8.0 Hz, 1H), 7.84-7.88 (m, 1H), 7.46 (d, J=7.5 Hz, 1H), 5.81(s, 1H), 3.15-3.25 (m, 4H), 2.76-2.86 (m, 1H), 2.56-2.67 (m, 1H),1.99-2.10 (m, 2H), 1.83-1.93 (m, 3H), 0.98 (s, 1H) 0.54 (s, 2H), 0.24(s, 2H).

EXAMPLE 412-(1-isobutylpiperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 22, substitutingEXAMPLE 35 for EXAMPLE 19. The crude product was purified by flashchromatography on silica gel with 0-10% methanol/dichloromethane/0.1%ammonium hydroxide. ¹H NMR (DMSO-d₆) δ 12.15 (s, 1H), 8.13 (d, J=6.8 Hz,1H), 8.00 (d, J=8.3 Hz, 1H), 7.84-7.89 (m, 1H), 7.46 (t, J=7.1 Hz, 1H),5.81 (s, 1H), 3.56 (s, 1H), 3.17 (d, J=5.2 Hz, 1H), 2.90-3.01 (m, 4H),2.12 (s, 3H), 2.07 (s, 2H), 1.86-1.94 (m, 1H), 0.97 (s, 6H).

EXAMPLE 422-(1-isopropylpiperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 28, substitutingEXAMPLE 35 for EXAMPLE 19. ¹H NMR (CD₃OD) δ 8.22 (d, J=8.0 Hz, 1H), 8.11(d, J=8.3 Hz, 1H), 7.82-7.88 (m, 1H), 7.47 (t, J=7.7 Hz, 1H), 5.91 (s,1H), 3.48-3.58 (m, 4H), 3.22 (s, 2H), 2.34 (s, 2H), 2.14 (s, 2H), 1.39(d, J=6.8 Hz, 7H).

EXAMPLE 43 2-pyrrolidin-3-yl-4H-pyrazolo[1,5-a]quinazolin-5-one EXAMPLE43A benzyl 3-(2-cyanoacetyl)pyrrolidine-1-carboxylate

A mixture of benzyl 3-carbomethoxypyrrolidine-1-carboxylate (1 g, 4mmol) and thionyl chloride (5 mL) was heated at reflux for 10 minutesand stirred overnight at ambient temperature. The mixture wasconcentrated, dried and substituted for cyclopropanecarbonyl chloride inEXAMPLE 32A to provide the title compound.

EXAMPLE 43B 2-pyrrolidin-3-yl-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 1, substitutingEXAMPLE 43A for 3-oxo-2-phenylpropionitrile. ¹H NMR (CD₃OD) δ 8.21-8.24(m, 1H), 8.15 (d, J=8.3 Hz, 1H), 7.86 (td, J=7.8, 1.5 Hz, 1H), 7.46-7.51(m, 1H), 5.97 (s, 1H), 3.73-3.79 (m, 1H), 3.66 (d, J=6.8 Hz, 2H), 3.50(s, 1H), 3.42-3.47 (m, 1H), 2.46-2.52 (m, 1H), 2.27-2.33 (m, 1H).

EXAMPLE 44 benzyl3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)pyrrolidine-1-carboxylate

The filtrate from EXAMPLE 43B was concentrated and purified by flashchromatography on silica gel with 10% methanol/dichloromethane toprovide the title compound. ¹H NMR (DMSO-d₆) δ 8.11 (s, 1H), 7.99 (s,1H), 7.84 (s, 1H), 7.44 (s, 1H), 7.33 (s, 5H), 5.85 (s, 1H), 5.08 (s,2H), 3.75 (s, 1H), 3.49 (s, 1H), 2.27 (s, 1H), 2.09 (s, 1H).

EXAMPLE 452-(1-methylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 20, substitutingEXAMPLE 43B for EXAMPLE 19. The crude product was purified by flashchromatography on silica gel with 0-10% methanol/dichloromethane/0.1%ammonium hydroxide. ¹H NMR (CD₃OD) δ 8.22 (dd, J=7.8, 1.7 Hz, 1H), 8.14(d, J=8.3 Hz, 1H), 7.86 (td, J=7.8, 1.5 Hz, 1H), 7.45-7.51 (m, 1H), 5.97(s, 1H), 3.81-3.89 (m, 1H), 3.66-3.74 (m, 2H), 3.44-3.56 (m, 2H), 3.00(s, 3H), 2.54-2.64 (m, 1H), 2.36 (ddd, J=14.9, 13.4, 6.8 Hz, 1H).

EXAMPLE 46 2-(1-ethylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 21, substitutingEXAMPLE 43B for EXAMPLE 19. The crude product was purified by flashchromatography on silica gel with 0-10% methanol/dichloromethane/0.1%ammonium hydroxide. ¹H NMR (CD₃OD) δ 8.18-8.24 (m, 1H), 8.10 (d, J=8.2Hz, 1H), 7.81-7.88 (m, 1H), 7.46 (t, J=7.6 Hz, 1H), 5.92 (s, 1H),3.57-3.65 (m, 1H), 3.28 (s, 1H), 3.00-3.08 (m, 1H), 2.87-2.97 (m, 2H),2.75-2.84 (m, 2H), 2.36-2.44 (m, 1H), 2.16 (td, J=13.8, 7.2 Hz, 1H),1.18-1.25 (m, 3H).

EXAMPLE 472-(1-cyclopropylmethylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 23, substitutingEXAMPLE 43B for EXAMPLE 19. The crude product was purified by flashchromatography on silica gel with 0-10% methanol/dichloromethane/0.1%ammonium hydroxide. ¹H NMR (CD₃OD) δ 8.21 (dd, J=8.0, 1.5 Hz, 1H), 8.10(d, J=8.3 Hz, 1H), 7.82-7.87 (m, 1H), 7.45 (t, J=7.7 Hz, 1H), 5.92 (s,1H), 3.54-3.62 (m, 1H), 3.28 (d, J=8.3 Hz, 2H), 3.01 (ddd, J=9.74 7.8,6.1 Hz, 1H), 2.78-2.85 (m, 3H), 2.33-2.40 (m, 1H), 2.08-2.17 (m, 1H),0.92-1.02 (m, 1H), 0.53-0.60 (m, 2H), 0.17-0.24 (m, 2H).

EXAMPLE 48 2-piperidin-2-yl-4H-pyrazolo[1,5-a]quinazolin-S -one EXAMPLE48A benzyl 2-(2-cyanoacetyl)piperidine-1-carboxylate

The title compound was prepared as described in EXAMPLE 43A,substituting benzyl-2-carbomethoxypiperidin-1-carboxylate for benzyl3-carbomethoxypyrrolidine-1-carboxylate.

EXAMPLE 48B 2-piperidin-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 1, substitutingEXAMPLE 48A for 3-oxo-2-phenylpropionitrile. ¹H NMR (CD₃OD) δ 8.18-8.27(m, 2H), 7.87-7.92 (m, 1H), 7.50-7.56 (m, 1H), 6.07 (s, 1H), 4.46 (dd,J=1.8, 3.2 Hz, 1H), 3.49 (s, 2H), 3.19 (td, J=12.6, 3.1 Hz, 1H),2.29-2.37 (m, 1H), 1.94-2.04 (m, 3H), 1.75-1.85 (m, 2H).

EXAMPLE 49 2-(1-methylpiperidin-2-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 20, substitutingEXAMPLE 48B for EXAMPLE 19. The crude product was purified by flashchromatography on silica gel with 0-10% methanol/dichloromethane/0.1%ammonium hydroxide. ¹H NMR (CD₃OD) δ 8.24 (dd J=7.9, 1.2 Hz, 1H), 8.15(d, J=8.2 Hz, 1H), 7.85-7.90 (m, 1H), 7.50 (t, J=7.6 Hz, 1H), 6.05 (s,1H), 3.55-3.63 (m, 1H), 3.49 (q, J=7.0 Hz, 1H), 3.24-3.30(m, 1H), 2.60(td, J=12.0, 3.5 Hz, 1H), 2.4 (s, 3H), 1.90-1.94 (m, 2H), 1.82-1.89 (m,2H), 1.52-1.62 (m, 1H), 1.18 (t, J=7.0 Hz, 1H).

EXAMPLE 50(S)-2-acetylamino-4-methyl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)pentanamideEXAMPLE 50A 3-aminomethyl-4H-pyrazolo[1,5-a]quinazolin-5-one

A suspension of 1.5 g of 3-cyano-4H-pyrazolo[1,5-a]quinazolin-5-one in150 mL of 20% ammonia in methanol was shaken with 15 g of aqueous Raneynickel at ambient temperature under 60 psi of hydrogen for 70 minutes.The suspension was diluted with 150 mL of methanol and warmed todissolve the precipitated product. Filtration through a nylon membraneand concentration of the filtrate yielded the title compound. MS(ESI)m/z 198 (M+H−NH3)⁺.

EXAMPLE 50B(S)-2-acetylamino-4-methyl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)pentanamide

To a microwave vial containing 125 mg ofpolystyrene-1,3-dicyclohexylcarbodiimide resin (Argonaut Technologies,1.2 mmol/g) was added N-acetyl-L-leucine (10.4 mg, 0.06 mmol) inN,N′-dimethylacetamide (0.3 mL). A solution of 1-hydroxybenzotriazole(6.8 mg, 0.05 mmol) in N,N′-dimethylacetamide (0.7 mL) was added,followed by the addition of diisopropylethylamine (27.7 μL, 0.15 mmol)in N,N′-dimethylacetamide (0.7 mL), and EXAMPLE 50A (11.2 mg, 0.05 mmol)in N,N′-dimethylacetamide (1 mL). The mixture was heated in a microwaveat 130° C. for 10 minutes, MP-carbonate (macroporous polystyreneanion-exchange resin, Argonaut Technologies) was added and the mixtureshaken overnight. The mixture was filtered, concentrated and the residuedissolved in 1:1 dimethylsulfoxide/methanol and purified by HPLC on aC18 column with 0-100% acetonitrile/water/0.1% trifluoroacetic acid togive the title compound. ¹H NMR (DMSO-d₆) δ 0.80 (d, 3H), 0.87 (d, 3H),1.43 (t, 2H), 1.49-1.60 (m, 1H), 1.83-1.88 (m, 3H), 4.17-4.21 (m, 2H),4.24 (t, 1H), 7.51 (t, 1H), 7.65-7.73 (m, 1H), 7.91 (t, 1H), 8.07 (d,1H).

EXAMPLE 51(R)-2-methoxy-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-2-phenylacetamide

The title compound was prepared as described in EXAMPLE 50 using(R)-(-)-α-methoxyplienylacetic acid in place of N-acetyl-L-leucine. ¹HNMR (DMSO-d₆) δ 3.24-3.32 (m, 3H), 4.21-4.25 (m, 2H), 4.61-4.70 (m, 1H),7.27-7.39 (m, 5H), 7.51 (t, 1H), 7.62-7.67 (m, 1H), 7.90 (t, 1H), 8.06(d, 1H), 8.16 (d, 1H).

EXAMPLE 52N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)isonicotinamide

The title compound was prepared as the trifluoroacetate salt asdescribed in EXAMPLE 50 using pyridine-4-carboxylic acid in place ofN-acetyl-L-leucine. ¹H NMR (DMSO-d₆) δ 4.46-4.48 (m, 2H), 7.55 (t, 1H),7.73-7.76 (m, 1H), 7.76-7.79 (m, 2H), 7.82-7.84 (m, 1H), 7.93 (t, 1H),8.10 (d, 1H), 8.19 (d, 1H), 8.68-8.71 (m, 1H), 8.71-8.75 (m, 2H).

EXAMPLE 53N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-3-piperidin-1-yl-propionamide

The title compound was prepared as the trifluoroacetate salt asdescribed in EXAMPLE 50 using 3-piperidinopropionic acid in place ofN-acetyl-L-leucine. ¹H NMR (DMSO-d₆) δ 0.99-1.97 (m, 6H), 2.60-2.63 (m,1H), 2.67 (t, 1H), 2.80-3.03 (m, 2H), 3.30 (t, 2H), 3.34-3.53 (m, 2H),4.20-4.33 (m, 2H), 7.51-7.66 (m, 1H), 7.79-7.84 (m, 1H), 7.89-8.03 (m,1H), 8.12 (d, 1H), 8.22 (d, 1H).

EXAMPLE 54N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-3-pyrrolidin-1-yl-propionamide

The title compound was prepared as the trifluoroacetate salt asdescribed in EXAMPLE 50 using 3-pyrrolidinopropionic acid in place ofN-acetyl-L-leucine. ¹H NMR (DMSO-d₆) δ 1.77-1.95 (m, 2H), 1.99-2.11 (m,2H), 2.58-2.60 (m, 1H), 2.63 (t, 1H), 2.95-3.06 (m, 2H), 3.36 (t, 2H),3.46-3.59 (m, 2H), 4.24-4.31 (m, 2H), 7.47-7.63 (m, 1H), 7.77-7.82 (m,1H), 7.90-7.98 (m, 1H), 8.05-8.15 (m, 1H), 8.15-8.23 (m, 1H).

EXAMPLE 552-morpholin-4-yl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)acetamide

The title compound was prepared as the trifluoroacetate salt asdescribed in EXAMPLE 50 using morpholin-4-yl-acetic acid in place ofN-acetyl-L-leucine. ¹H NMR (DMSO-d₆) δ 2.97-3.34 (m, 4H), 3.65-3.95 (m,6H), 4.26-4.38 (m, 2H), 7.53 (t, 1H), 7.75-7.83 (m, 1H), 7.92 (t, 1H),8.08 (d, 1H), 8.20 (d, 1H).

EXAMPLE 563-morpholin-4-yl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-propionamide

The title compound was prepared as the trifluoroacetate salt asdescribed in EXAMPLE 50 using 3-morpholinopropionic acid in place ofN-acetyl-L-leucine. ¹H NMR (DMSO-d₆) δ 2.58-2.60 (m, 1H), 2.64 (t, 2H),2.78-3.96 (m, 9H), 4.23-4.31 (m, 2H), 7.54 (t, 1H), 7.74-7.82 (m, 1H),7.93 (t, 1H), 8.08 (d, 1H), 8.18 (d, 1H).

EXAMPLE 57 2-phenethyl-4H-pyrazolo[1,5-a]quinazolin-5-one EXAMPLE 57A3-oxo 5-phenyl-pentanenitrile

A solution of cyanoacetic acid (1.0 g, 11.8 mmol) in tetrahydrofuran (20mL) was cooled to −78° C. and treated with 1.6 M n-butyl lithium inhexanes (14.7 mL, 23.5 mmol). The mixture was warmed to −20° C. over 2hours, cooled to -78° C. and treated with 3-phenylpropionyl chloride(prepared by refluxing a solution of 3-phenylpropionic acid (1.0 g, 6.7mmol) in thionyl chloride (4 mL) for 3 hours, evaporating and drying).The mixture was stirred at −78° C. for 1 hour and 20% hydrochloric acidadded until the pH=3. The mixture was diluted with diethyl ether, washedwith saturated sodium bicarbonate, and the organic layer separated andconcentrated. The crude product was purified by flash chromatography onsilica gel using 0-50% ethyl acetate/hexanes to provide the titlecompound. MS (ESI) m/e 191 (M+H+NH₃).

EXAMPLE 57B 2-phenethyl-4H-pyrazolo[1,5-a]quinazolin-5-one

A mixture of 2-hydrazinobenzoic acid (0.17 g, 0.9 mmol) and EXAMPLE 57A(0.155 g, 0.9 mmol) in acetic acid (3 mL) was heated in a microwave at150° C. for 10 minutes. The precipitated product was washed withmethanol and diethyl ether and dried. ¹H NMR (DMSO-d₆) δ 12.10 (s, 1H),8.09-8.14 (m, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.82-7.88 (m, 1H), 7.44 (t,J=7.6 Hz, 1H), 7.26-7.32 (m, 4H), 7.16-7.22 (m, 1H), 5.78 (s, 1H),2.92-3.01 (m, 4H).

EXAMPLE 58 2-benzyl-4H-pyrazolo[1,5-a]quinazolin-5-one EXAMPLE 58A3-oxo-4-phenyl-butyronitrile

The title compound was prepared as described in EXAMPLE 57A,substituting phenylacetyl chloride for 3-phenylpropionyl chloride. MS(ESI) m/e 177 (M+H+NH₃)⁺.

EXAMPLE 58B 2-benzyl-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 57B,substituting EXAMPLE 58A for EXAMPLE 57A. The crude product was purifiedby flash chromatography on silica gel with 50% ethyl acetate/hexanes. ¹HNMR (DMSO-d₆) δ 8.11 (dd, J=7.9, 1.2 Hz, 1H), 8.04 (d, J=8.2 Hz, 1H),7.82-7.89 (m, 1H), 7.42-7.49 (m, 1H), 7.29-7.33 (m, 4H), 7.22 (td,J=5.6, 2.8 Hz, 1H), 5.67 (s, 1H), 3.99 (s, 2H).

EXAMPLE 59 2-piperidin-4-ylmethyl-4H-pyrazolo[1,5-a]quinazolin-5-oneEXAMPLE 59A tert-butyl 4-(3-cyano-2-oxopropyl)piperidine-1-carboxylate

A solution of tert-butyl 4-carboxymethylpiperidine-1-carboxylate (1 g,4.1 mmol) in tetrahydrofuran (5 mL) was treated with1,1′-carbonyldiimidazole (0.67 g, 4.1 mmol). The mixture was heated at55° C. for 2 hours, cooled and submitted to the conditions described inEXAMPLE 57A, substituting the solution obtained above for3-phenylpropionyl chloride. MS (ESI) m/e 284 (M+H+NH₃)⁺.

EXAMPLE 59B 2-piperidin-4-ylmethyl-4H-pyrazolo[1,5-a]quinazolin-5-one

The title compound was prepared as described in EXAMPLE 57B,substituting EXAMPLE 59A for EXAMPLE 57A. The crude product was purifiedby flash chromatography on silica gel with 10%methanol/dichloromethane/0.1% ammonium hydroxide. ¹H NMR (DMSO-d₆) δ8.11 (dd, J=7.9, 1.2 Hz, 1H), 8.00 (d, J=7.9 Hz, 1H), 7.78-7.85 (m, 1H),7.43 (t, J=7.5 Hz, 1H), 5.72 (s, 1H), 3.35-3.39 (m, 1H), 3.17 (s, 1H),2.91 (d, J=11.9 Hz, 2H), 2.40-2.49 (m, 3H), 1.65-1.74 (m, 1H), 1.60 (d,J=11.9 Hz, 2H), 1.05-1.14 (m, 2H).

EXAMPLE 602-(1-methylpiperidin-4-ylmethyl)-4H-pyrazolo[1,5-a]quinazolin-5-one Asolution of

EXAMPLE 59 (0.034 g, 0.1 mmol) and 36% formaldehyde in water (0.05 mL,0.6 mmol) in methanol (2 mL) was treated with sodium cyanoborohydride(0.006 g, 0.1 mmol) and acetic acid (0.2 mL). The mixture was stirred atambient temperature for 2 hours and concentrated. The crude product waspurified by flash chromatography on silica gel with 10%methanol/dichloromethane to provide the title compound. ¹H NMR (DMSO-d₆)δ 8.11 (d, J=7.7 Hz, 1H), 8.01 (d, J=8.3 Hz, 1H), 7.81-7.86 (m, 1H),7.44 (t, J=7.7 Hz, 1H), 5.74 (s, 1H), 2.72 (d, J=l 1.4 Hz, 2H), 2.54 (d,J=6.8 Hz, 2H) 2.13 (s, 3H), 1.82 (s, 2H), 1.54-1.66 (m, 3H), 1.18-1.29(m, 2H).

EXAMPLE 61 2-(3-Bromobenzyl) pyrazolo[1,5-a]quinazolin-5(4H)-one EXAMPLE61A 4-(3-Bromophenyl)-3-oxobutanenitrile

The title compound was prepared as described in EXAMPLE 32A,substituting 2-(3-bromophenyl)acetyl) chloride-for cyclopropanecarbonylchloride.

EXAMPLE 61B 2-(3-Bromobenzyl) pyrazolo[1,5-a]quinazolin-5(4H)-one

The title compound was prepared as described in EXAMPLE 1, substitutingExample 61A for 3-oxo-2-phenylpropionitrile and using 3 mL of aceticacid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.01 (s, 2H) 5.73 (s, 1H)7.26-7.35 (m, 2H) 7.41-7.48 (m, 2H), 7.52-7.55 (m, 1H) 7.86 (dd, J=8.29,7.06 Hz, 1H) 8.03 (d, J=7.67 Hz, 1H) 8.12 (dd, J=7.98, 1.53 Hz, 1H)12.09 (s, 1H).

EXAMPLE 623-[(5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzonitrile

A mixture of Example 61B (0.075 g, 0.212 mmol), dicyanozinc (0.03 g,0.254 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.021mmol) in DMF (2 mL) was heated in a microwave (Personal ChemistrySmithSynthesizer) at 150° C. for 10 minutes. The mixture was evaporatedand purified by chromatography on silica gel with 10% MeOH/CH₂Cl₂ toprovide the desired product. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 4.08 (s,2H) 5.76 (s, 1H) 7.46 (t, J=7.63 Hz, 1H) 7.53 (t, J=7.63 Hz, 1H) 7.69(dd, J=12.36, 7.78 Hz, 2H) 7.79-7.88 (m, 2H) 8.02 (d, J=7.93 Hz, 1H)8.12 (d, J=7.93 Hz, 1H) 12.12 (s, 1H).

EXAMPLE 63 2-[3-(Aminomethyl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one

A mixture of Example 62 (0.32 g, 1.066 mmol) and 3 g raney-nickel inmethanol ammonia (30 mL) was stirred under a hydrogen atmosphere at 60psi for 3.5 hr. The mixture was filtered then evaporated and purified bychromatography on silica gel with 10% MeOH/CH₂Cl₂ to provide the desiredproduct. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.17 (s, 1H) 3.71 (s, 2H) 3.97(s, 2H) 5.66 (s, 1H) 7.14-7.20 (m, 2H) 7.22-7.29 (m, 2H) 7.42-7.47 (m,1H) 7.82-7.87 (m, 1H) 8.03 (d, J=8.29 Hz, 1H) 8.11 (dd, J=7.98, 1.53 Hz,1H).

EXAMPLE 64 2-(3-Pyridin-3-ylbenzyl)pyrazolo[1,5-a]quinazolin-5(4H)-one

A mixture of Example 61B (0.05 g, 0.141 mmol), pyridine-3-ylboronic acid(0.018 g, 0.148 mmol) cesium fluoride (0.064 g, 0.423 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.1 g, 0.014 mmol) in DME (2mL) was heated in a microwave (Personal Chemistry SmithSynthesizer) at150° C. for 10 minutes. The mixture was filtered evaporated. The residuewas purified by HPLC on a C18 column with 0-100% CH₃CN/H₂O/0.1% TFA toprovide the desired product. ¹H NMR (400 MIz, DMSO-d₆) δ ppm 4.10 (s,2H) 5.75 (s, 1H) 7.41-7.51 (m, 3H) 7.63-7.73 (m, 2H) 7.76 (s, 1H),7.83-7.88 (m, 1H) 8.04 (d, J=7.67 Hz, 1H) 8.12 (dd, J=8.13, 1.38Hz, 1H)8.35 (dt, J=7.98, 1.84 Hz, 1H) 8.68 (dd, J=5.06, 1.38 Hz, 1H) 9.01 (d,J=2.15 Hz, 1H) 12.08 (s, 1H).

EXAMPLE 652-[3-(2-Oxopyrrolidin-1-yl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one

A mixture of Example 61B (0.1 g, 0.282 mmol), pyrrolidin-2-one (0.048 g,0.565 mmol) cesium carbonate (0.130 g, 0.395 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.026 g, 0.028 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.025 g,0.043 mmol) in DME (2 mL) was heated in a microwave (Personal ChemistrySmithSynthesizer) at 200° C. for 60 minutes. The mixture was filteredevaporated. The residue was purified by chromatography on silica gelwith 20% to 80% ethyl acetate in hexane to provide the desired product.¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.01-2.08 (m, 2H) 2.47 (t, J=8.09 Hz,2H) 3.81 (t, J=7.02 Hz, 2H) 3.99 (s, 2H) 5.67 (s, 1H), 7.08 (d, J=7.63Hz, 1H) 7.30 (t, J=7.78 Hz, 1H) 7.43-7.50 (m, 2H) 7.66 (s, 1H) 7.80-7.88(m, 1H) 8.04 (d, J=8.24 Hz, 1H) 8.12 (d, J=7.93 Hz, 1H).

EXAMPLE 663′-[(5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]-1,1′-biphenyl-2-carbaldehyde

The title compound was prepared as described in EXAMPLE 64, substituting2-(formylphenyl)boronic acid-for pyridine-3-ylboronic acid. ¹H NMR (500MHz, DMSO-d₆) δ ppm 4.09 (s, 2H) 5.75 (s, 1H) 7.32 (d, J=7.02 Hz, 1H)7.40-7.49 (m, 4H), 7.52 (d, J=7.63 Hz, 1H) 7.56-7.61 (m, 1H) 7.75 (d,J=1.22 Hz, 1H) 7.85 (s, 1H) 7.88-7.95 (m, 1H) 8.04 (d, J=8.24 Hz, 1H)8.11 (dd, J=7.93, 1.53 Hz, 1H) 9.90 (s, 1H).

EXAMPLE 67 (A-998677.0)2-[3-(2-Fluoropyridin-4-yl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one

A mixture of Example 61B (0.1 g, 0.282 mmol),2-fluoro-4-(tributylstannyl)pyridine (0.11 g, 0.285 mmol) triethylamine(0.11 g, 1.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.039 g,0.01 mmol) and tri-o-tolylphosphine (0.007 g, 0.023 mmol) in DMF (2 mL)was heated at 100° C. for 6 hr. The mixture was diluted with EtOAc andwashed with sat NaHCO₃, H₂O and brine, then evaporated. The residue waspurified by chromatography on silica gel with 20% to 80% ethylacetate inhexane to provide the desired product. ¹H NMR (500 MHz, DMSO-d₆) δ ppm4.10 (s, 2H) 5.75 (s, 1H) 7.44-7.53 (m, 4H) 7.68-7.74 (m, 2H) 7.83-7.88(m, 2H) 8.04 (d, J=8.24 Hz, 1H) 8.11 (d, J=6.71 Hz, 1H) 8.30 (d, J=5.49Hz, 1H).

EXAMPLE 68 Methyl3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzoate

A mixture of Example 61B (0.25 g, 0.706 mmol) triethylamine (0.2 ml,1.542 mmol) anddichlorobis(diphenylphosphino)dipalladium(II)dichloromethane (0.03 g,0.041 mmol) in methanol (10 mL) under carbon monoxide at 50psi washeated at 100° C. for 3 hr. The mixture was filtered then evaporated andpurified by chromatography on silica gel with 10% MeOH/CH₂Cl₂ to providethe desired product. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 3.81-3.86 (m, 3H)4.09 (s, 2H) 5.71 (s, 1H) 7.44-7.50 (m, 2H) 7.62 (d, J=7.63 Hz, 1H)7.81-7.88 (m, 2H) 7.91 (s, 1H) 8.03 (d, J=7.63 Hz, 1H) 8.12 (dd, J=7.93,1.22 Hz, 1H).

EXAMPLE 693-[(4-Methylpiperazin-1-yl)carbonyl]pyrazolo[1,5-a]quinazolin-5(4H)-oneEXAMPLE 69A 5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxylicacid

A mixture of 2-hydrazinylbenzoic acid hydrochloride (1.05 g, 5.57 mmol),(E)-ethyl 2-cyano-3-ethoxyacrylate (0.9 g, 5.32 mmol) and sodium acetate(0.457 g, 5.57 mmol) in DMF (7 mL) was heated to 140° C. for 2 h thencooled. Water (5 mL) was added and the mixture was stirred at rt for 1 hthen filtered. The solid was washed with H₂O, EtOH and Et₂O then dried.The solid was dissolved in EtOH (10 mL), treated with a 1M solution ofsodium hydroxide (23 mL, 23 mmol) and the mixture was heated at 80° C.for 18 hr. The mixture was filtered hot then cooled and acidified withacetic acid and 10% HCl. The precipitated product was filtered, washedwith H₂O and Et₂O, dried well and used without any further purification.

EXAMPLE 69B3-[(4-Methylpiperazin-1-yl)carbonyl]pyrazolo[1,5-a]quinazolin-5(4H)-one

A mixture Example 69A (0.1 g, 0.44 mmol), 1-methyl piperazine (0.045 g,0.45 mmol) and CDI (0.075 g, 0.53 mmol) in DMF (1 mL) and pyridine (1mL) was stirred overnight at ambient temperature. The mixture wasevaporated and purified by chromatography on silica gel with 10%MeOH/CH₂Cl₂ to provide the desired product. ¹H NMR (500 MHz, DMSO-d₆) δppm 2.38 (s, 3H) 2.58 (s, 4H) 3.65-3.70 (m, 4H) 7.15 (s, 1H) 7.56 (t,J=7.48 Hz, 1H) 7.88-7.96 (m, 1H) 8.07 (s, 1H) 8.12 (d, J=8.24 Hz, 1H)8.18 (d, J=7.02 Hz, 1H).

EXAMPLE 70 3-(Pyrrolidine-1-carbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one

The title compound was prepared as described in Example 69B,substituting pyrrolidine for 1-methyl piperazine in Example 69 B. Themixture was evaporated and purified by chromatography on silica gel with10% MeOH/CH₂Cl₂ to provide the desired product. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.85 (s, 2H) 1.99 (s, 2H) 3.50 (s, 2H) 3.75 (s, 2H) 7.59(s, 1H) 7.96 (s, 1H) 8.14 (d, J=8.24 Hz, 1H) 8.20 (d, J=7.93 Hz, 1H),8.25 (s, 1H).

EXAMPLE 71N,N-Dimethyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide

The title compound was prepared as described in Example 69B,substituting dimethylamine for 1-methyl piperazine in Example 69B. Themixture was evaporated and purified by chromatography on silica gel with10% MeOH/CH₂Cl₂ to provide the desired product. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 3.32 (s, 6H) 7.57 (t, J=7.48 Hz, 1H) 7.92-7.97 (m, 1H)8.12-8.20 (m, 3H) 11.32 (s, 1H).

EXAMPLE 72 3-(Piperidine-1-carbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one

The title compound was prepared as described in Example 69B,substituting piperidine for 1-methyl piperazine in Example 69B. Themixture was evaporated and purified by chromatography on silica gel with10% MeOH/CH₂Cl₂ to provide the desired product. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.51-1.57 (m, 4H) 1.60-1.67 (m, 2H) 3.56-3.61 (m, 4H)7.56 (t, J=7.63 Hz, 1H) 7.90-7.95 (m, 1H) 8.04 (s, 1H) 8.12 (d, J=7.93Hz, 1H), 8.15-8.20 (m, 1H) 11.58 (s, 1H).

EXAMPLE 73N-Cyclopropyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide

The title compound was prepared as described in Example 69B,substituting cyclopropylamine for 1-methyl piperazine in Example 69 B.The mixture was evaporated and purified by chromatography on silica gelwith 10% MeOH/CH₂Cl₂ to provide the desired product. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.56 (ddd, J=6.67, 4.45, 4.22 Hz, 2H) 0.72 (td, J=6.98,5.06 Hz, 2H) 2.82 (ddd, J=7.44, 3.61, 3.38 Hz, 1H) 7.53-7.59 (m, 1H)7.89-7.97 (m, 1H) 8.10 (d, J=7.98 Hz, 1H) 8.19 (dd, J=7.98, 1.23 Hz, 1H)8.26 (s, 1H), 8.34 (d, J=3.38 Hz, 1H) 10.69 (s, 1H).

EXAMPLE 74 5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide

The title compound was prepared as described in Example 69B,substituting ammonia for 1-methyl piperazine in Example 69B. The mixturewas evaporated and purified by chromatography on silica gel with 10%MeOH/CH₂Cl₂ to provide the desired product. ¹H H NMR (400 MHz, DMSO-d₆)δ ppm 7.32 (s, 1H) 7.54-7.63 (m, 1H) 7.84 (s, 1H) 7.90-7.97 (m, 1H) 8.11(d, J=8.29 Hz, 1H) 8.19 (dd, J=7.98, 1.23 Hz, 1H) 8.29 (s, 1H) 10.62 (s,1H)

EXAMPLE 75N-Methyl-5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide

The title compound was prepared as described in Example 69B,substituting methanamine for 1-methyl piperazine in Example 69B. Themixture was evaporated and purified by chromatography on silica gel with10% MeOH/CH₂Cl₂ to provide the desired product. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 2.78 (d, J=4.58 Hz, 3H) 7.57 (t, J=7.63 Hz, 1H) 7.91-7.96(m, 1H) 8.10 (d, J=8.24 Hz, 1H) 8.18 (d, J=7.63 Hz, 1H) 8.26 (s, 1H),8.31 (d, J=4.58 Hz, 1H) 10.70 (s, 1H).

EXAMPLE 76N-Ethyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide

The title compound was prepared as described in Example 69B,substituting ethanamine for 1-methyl piperazine in Example 69B. Theresidue was purified by HPLC on a C18 column with 0-100% CH₃CN/H₂O/0.1%TFA to provide the desired product as the trifluoroacetate salt. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 1.14 (t, J=7.17 Hz, 3H) 3.23-3.30 (m, 2H)7.54-7.60 (m, 1H) 7.91-7.97 (m, 1H) 8.09-8.14 (m, 2H) 8.19 (dd, J=7.48,2.59 Hz, 1H) 8.29-8.36 (m, 1H).

EXAMPLE 77N-Benzyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide

The title compound was prepared as described in Example 69B,substituting phenylmethanamine for 1-methyl piperazine in Example 69B.The residue was purified by HPLC on a C18 column with 0-100%CH₃CN/H₂O/0.1% TFA to provide the desired product as thetrifluoroacetate salt. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 4.49 (d, J=5.80Hz, 2H) 7.23-7.31 (m, 1H) 7.35 (d, J=4.27 Hz, 4H) 7.57 (t, J=7.17 Hz,1H) 7.91-7.97 (m, 1H), 8.11 (d, J=7.63 Hz, 1H) 8.19 (dd, J=7.93, 1.22Hz, 1H) 8.36 (s, 1H) 8.90 (t, J=5.95 Hz, 1H) 10.74 (s, 1H).

EXAMPLE 785-Oxo-N-(2-phenylethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide

The title compound was prepared as described in Example 69B,substituting phenethylamine for 1-methyl piperazine in Example 69B. Theresidue was purified by HPLC on a C18 column with 0-100% CH₃CN/H₂O/0.1%TFA to provide the desired product as the trifluoroacetate salt. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 2.82-2.89 (m, 2H) 3.45-3.51 (m, 2H) 7.21 (t,J=7.17 Hz, 1H) 7.25-7.33 (m, 4H) 7.57 (t, J=7.63 Hz, 1H) 7.91-7.97 (m,1H) 8.10 (d, J=7.93 Hz, 1H) 8.18 (dd, J=7.93, 1.22 Hz, 1H) 8.30 (s, 1H)8.48 (t, J=5.49 Hz, 1H).

EXAMPLE 79 3-(Azepane-1-carbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one

The title compound was prepared as described in Example 69B,substituting azepane for 1-methyl piperazine in Example 69 B. Themixture was evaporated and purified by chromatography on silica gel with10% MeOH/CH₂Cl₂ to provide the desired product. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.51-1.57 (m, 4H) 1.75 (s, 4H) 3.57 (s, 2H) 3.70 (s, 2H)7.57 (t, J=7.63 Hz, 1H) 7.92-7.97 (m, 1H) 8.09-8.15 (m, 2H) 8.18-8.20(m, 1H) 11.29 (s, 1H).

EXAMPLE 80 3-(Morpholine-4-carbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one

The title compound was prepared as described in Example 69B,substituting morpholine for 1-methyl piperazine in Example 69B. Themixture was evaporated and purified by chromatography on silica gel with10% MeOH/CH₂Cl₂ to provide the desired product. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 3.34 (s, 8H) 7.54-7.58 (m, 1H) 7.91-7.95 (m, 1H)8.08-8.13 (m, 2H) 8.16-8.19 (m, 1H).

EXAMPLE 81 3-(Piperazin-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one

The title compound was prepared as described in Example 69B,substituting tert-butyl piperazine-1-carboxylate for 1-methyl piperazinein Example 69 B. The reaction mix was evaporated then treated with 1 mLCH₂Cl₂ and 1 mL of TFA and stirred for 1 hr then evaporated. The mixturewas evaporated and purified by chromatography on silica gel with 10%MeOH/CH₂Cl₂/0.1% NH₄OH to provide the desired product. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 2.84-2.90 (m, 4H) 3.60-3.66 (m, 4H) 7.54 (t, J=7.48 Hz,1H) 7.89-7.94 (m, 1H) 8.05 (s, 1H) 8.11 (d, J=8.24 Hz, 1H) 8.17 (d,J=7.93 Hz, 1H)

EXAMPLE 82N-Cyclohexyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide

The title compound was prepared as described in Example 69B,substituting cyclohexylamine for 1-methyl piperazine in Example 69 B.The mixture was evaporated and purified by chromatography on silica gelwith 10% MeOH/CH₂Cl₂ to provide the desired product. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.11-1.19 (m, 1H) 1.25-1.34 (m, 4H) 1.62 (d, J=12.82 Hz,1H) 1.71-1.78 (m, 2H) 1.85 (d, J=8.85 Hz, 2H) 3.77 (dd, J=7.48, 3.81 Hz,1H) 7.56 (t, J=7.63 Hz, 1H) 7.91-7.96 (m, 1H) 8.11 (t, J=8.24 Hz, 2H)8.18 (d, J=7.93 Hz, 1H).

EXAMPLE 833-(1H-Imidazol-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one

The title compound was prepared as described in Example 69B,substituting pyridin-4-amine for 1-methyl piperazine in Example 69 B.The mixture was evaporated and purified by chromatography on silica gelwith 10% MeOH/CH₂Cl₂ to provide the desired product. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 7.18 (s, 1H) 7.63 (t, J=7.63 Hz, 1H) 7.85 (s, 1H)7.96-8.02 (m, 1H) 8.20 (dd, J=19.68, 7.48 Hz, 2H) 8.45-8.50 (m, 2H).

EXAMPLE 845-Oxo-N-(piperidin-4-ylmethyl-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide

The title compound was prepared as described in Example 69, substitutingtert-butyl 4-(aminomethyl)piperidine-1-carboxylate for 1-methylpiperazine in Example 69 B. The reaction mix was evaporated then treatedwith 1 mL CH₂Cl₂ and 1 mL of TFA and stirred for 1 hr then evaporated.The residue was purified by HPLC on a C18 column with 0-100%CH₃CN/H₂O/0.1% TFA to provide the desired product as thetrifluoroacetate salt. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.34 (d, J=12.21Hz, 2H) 1.82 (s, 3H) 2.87 (s, 2H) 3.16-3.21 (m, 3H) 7.58 (t, J=7.63 Hz,1H) 7.93-7.97 (m, 1H) 8.11 (d, J=7.63 Hz, 1H) 8.19 (dd, J=7.93, 1.22 Hz,1H) 8.45 (t, J=5.80 Hz, 2H).

EXAMPLE 853-(3-(Aminomethyl)piperidine-1-carbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one

The title compound was prepared as described in Example 69B,substituting tert-butyl piperidin-3-ylmethylcarbamate for 1-methylpiperazine in Example 69 B. The reaction mix was evaporated then treatedwith 1 mL CH₂Cl₂ and 1 mL of TFA and stirred for 1 hr then evaporated.The residue was purified by HPLC on a C18 column with 0-100%CH₃CN/H₂O/0.1% TFA to provide the desired product as thetrifluoroacetate salt. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.26-1.36 (m, 1H)1.39-1.50 (m, 1H) 1.66-1.75 (m, 1H) 1.80-1.91 (m, 2H) 2.78 (qd, J=12.79,7.06 Hz, 2H) 2.93 (s, 1H) 3.38-3.41 (m, 1H) 4.14 (s, 2H) 7.53-7.62 (m,1H) 7.91-7.97 (m, 1H) 8.06 (s, 1H) 8.10-8.21 (m, 2H).

EXAMPLE 865-Oxo-N-phenyl-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide

The title compound was prepared as described in Example 69B,substituting aniline for 1-methyl piperazine in Example 69 B. Themixture was evaporated and purified by chromatography on silica gel with10% MeOR/CH₂Cl₂ to provide the desired product. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.11 (t, J=7.36 Hz, 1H) 7.37 (t, J=7.98 Hz, 2H) 7.59 (t,J=7.67 Hz, 1H) 7.73 (d, J=7.67 Hz, 2H) 7.93-7.99 (m, 1H) 8.13-8.23 (m,2H) 8.53 (s, 1H) 10.05 (s, 1H) 10.93 (s, 1H).

EXAMPLE 874-{[(5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)carbonyl]amino}butanoicacid

The title compound was prepared as described in Example 69B,substituting 4-aminobutanoic acid for 1-methyl piperazine in Example 69B. The mixture was evaporated and purified by chromatography on silicagel with 10% MeOH/CH₂Cl₂ to provide the desired product. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.76 (dq, J=7.36, 7.16 Hz, 2H) 2.30 (t, J=7.36 Hz,2H) 3.25-3.30 (m, 2H) 7.56 (t, J=7.67 Hz, 1H) 7.89-7.96 (m, 1H) 8.10 (d,J=7.67 Hz, 1H) 8.18 (dd, J=7.98, 1.23 Hz, 1H) 8.29 (s, 1H) 8.34-8.38 (m,1H).

EXAMPLE 88 3-(5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl)benzoic acid

Example 68 (0.15 g, 0.45 mmol) was dissolved in EtOH (10 mL), treatedwith a 1M solution of sodium hydroxide (3 mL, 3 mmol) and the mixturewas heated at 80° C. for 18 hr. The mixture was filtered then acidifiedwith acetic acid and 10% HCl. The precipitated product was filtered,washed with H₂O and Et₂O then dried well. ¹H NMR (500 MHz, DMSO-d₆) δppm 4.04-4.11 (m, 2H) 5.71 (s, 1H) 7.45 (td, J=7.63, 4.58 Hz, 2H) 7.59(d, J=8.24 Hz, 1H) 7.80 (d, J=7.63 Hz, 1H) 7.84-7.90 (m, 2H) 8.04 (d,J=8.24 Hz, 1H) 8.12 (d, J=7.02 Hz, 1H) 12.11 (s, 1H) 12.93 (s, 1H).

EXAMPLE 89 5-Oxo-N-(2-(piperidin-1-yl)ethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide

The title compound was prepared as described in Example 69B,substituting 2-(piperidin-1-yl)ethanamine for 1-methyl piperazine inExample 69B. The mixture was evaporated and purified by chromatographyon silica gel with 10% MeOH/CH₂Cl₂ to provide the desired product. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 1.39-1.41 (m, 1H) 1.64-1.73 (m, 3H) 1.84(d, J=14.34 Hz, 2H) 2.92-3.00 (m, 2H) 3.24 (q, J=5.80 Hz, 2H) 3.56 (d,J=11.60 Hz, 2H) 3.63 (q, J=6.10 Hz, 2H) 7.59 (t, J=7.63 Hz, 1H)7.93-7.99 (m, 1H) 8.12 (d, J=7.93 Hz, 1H) 8.20 (dd, J=7.93, 1.22 Hz, 1H)8.29 (s, 1H) 8.68 (t, J=5.65 Hz, 1H) 10.81 (s, 1H).

EXAMPLE 90 3-(Hydroxymethyl)pyrazolo[1,5-a]quinazolin -5-(4H)-oneEXAMPLE 90A Methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxylate

A mixture of 2-hydrazinylbenzoic acid hydrochloride (1.05 g, 5.57 mmol),(E)-ethyl 2-cyano-3-ethoxyacrylate (0.9 g, 5.32 mmol) and sodium acetate(0.457 g, 5.57 mmol) in DMF (7 mL) was heated to 140° C. for 2 h thencooled. Water (5 mL) was added and the mixture was stirred at ambienttemperature for 1 h then filtered. The solid was washed with H₂O, EtOHand Et₂O then dried.

EXAMPLE 90B 3-(Hydroxymethyl)pyrazolo[1,5-a]quinazolin -5-(4H)-one

A mixture Example 90A (0.1 g, 0.39 mmol) and lithium aluminum hydride(0.044 g, 1.16 mmol) in THF (5 mL) was refluxed for 3 h then cooled andquenched with water and 15% NaOH. The mixture was filtered, evaporatedand purified by chromatography on silica gel with 10% MeOH/CH₂Cl₂ toprovide the desired product. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 4.47 (s,2H) 7.46-7.52 (m, 1H) 7.78 (s, 1H) 7.83-7.91 (m, 1H) 8.07 (d, J=7.93 Hz,1H) 8.14 (dd, J=7.93, 1.22 Hz, 1H) 12.15 (s, 1H).

EXAMPLE 91 3-(5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl)benzamide

A mixture Example 88 (0.15 g, 0.47 mmol), 2M solution of NH₃ in MeOH(0.5 mL, 0.1 mmol) and CDI (0.076 g, 0.54 mmol) in DMF (1 mL) andpyridine (1 mL) was stirred overnight at ambient temperature thenevaporated. The residue was purified by HPLC on a C18 column with 0-100%CH₃CN/H₂O/0.1% TFA to provide the desired product as thetrifluoroacetate salt. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 4.04 (s, 2H) 5.69(s, 1H) 7.33 (s, 1H) 7.39 (t, J=7.63 Hz, 1H) 7.44-7.49 (m, 2H) 7.73 (d,J=7.63 Hz, 1H) 7.81-7.89 (m, 2H) 7.95 (s, 1H) 8.04 (d, J=7.93 Hz, 1H)8.11 (dd, J=7.93, 1.22 Hz, 1H) 12.11 (s, 1H).

EXAMPLE 92 3-(Aminomethyl)pyrazolo[1,5-a]quinazolin -5-(4H)-one EXAMPLE92A Methyl -5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxylate

A mixture of 2-hydrazinylbenzoic acid hydrochloride (10 g, 53 mmol),2-(ethoxymethylene)malononitrile (6.5 g, 53.2 mmol) and sodium ethoxide(4.85 g, 257 mmol) in EtOH (100 mL) was refluxed overnight then cooledto ambient temperature. Water was added and the mixture was stirred atambient temperature for 1 h then filtered. The solid was washed withH₂O, EtOH and Et₂O then dried.

EXAMPLE 92B 3-(Aminomethyl)pyrazolo[1,5-a]quinazolin -5-(4H)-one

The title compound was prepared as described in Example 63. The residuewas purified by HPLC on a C18 column with 0-100% CH₃CN/H₂O/0.1% TFA toprovide the desired product as the trifluoroacetate salt. ¹H NMR (500MHz, DMSO-d₆) δ ppm 4.08 (s, 2H) 7.54 (t, J=7.63 Hz, 1H) 7.89 (s, 1H)7.90-7.94 (m, 1H) 8.00 (s, 1H) 8.11 (d, J=7.93 Hz, 1H) 8.18 (dd, J=7.93,1.22 Hz, 1H).

EXAMPLE 93N-[(5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]glycine

A mixture of Example 92B (0.1 g, 0.47 mmol), 2-oxoacetic acid (0.035 g,0.47 mmol) and sodium cyanoborohydride (0.029 g, 0.45 mmol) in MeOH (2mL) was refluxed overnight then evaporated. The residue was purified byHPLC on a C 18 column with 0-100% CH₃CN/H₂O/0.1% TFA to provide thedesired product as the trifluoroacetate salt. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 2.54 (s, 2H) 4.08 (q, J=5.42 Hz, 2H) 7.52-7.57 (m, 1H) 7.89-8.00(m, 4H) 8.11 (d, J=7.67 Hz, 1H) 8.18 (d, J=7.06 Hz, 1H) 12.34 (s, 1H).

EXAMPLE 944-Chloro-N-((5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl)butanamide

A mixture of Example 92B (0.1 g, 0.47 mmol), 4-chlorobutanoyl chloride(0.066 g, 0.47 mmol) in DMF (1 mL) and pyridine (1 mL) was stirredovernight at room temperature then evaporated. The residue was purifiedby HPLC on a C18 column with 0-100% CH₃CN/H₂O/0.1% TFA to provide thedesired product as the trifluoroacetate salt. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.92-2.00 (m, J=6.98, 6.98, 6.98, 6.98 Hz, 2H) 2.27 (t, J=7.36 Hz,2H) 3.63 (q, J=6.55 Hz, 2H) 4.21 (d, J=5.52 Hz, 2H) 7.47-7.53 (m, 1H)7.86-7.92 (m, 1H) 8.07 (d, J=7.98 Hz, 1H) 8.15 (dd, J=7.98, 1.23 Hz, 1H)11.96 (s, 1H).

EXAMPLE 954-Oxo-4-((5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methylamino)butanoicacid

A mixture of Example 92B (0.1 g, 0.47 mmol) and dihydrofuran-2,5-dione(0.047 g, 0.47 mmol) in CH₃CN (2 mL) was heated to 80° C. overnight thenevaporated. The residue was purified by HPLC on a C18 column with 0-100%CH₃CN/H₂O/0.1% TFA to provide the desired product as thetrifluoroacetate salt. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.35 (t, J=7.02Hz, 2H) 2.46 (t, J=6.71 Hz, 2H) 4.20 (d, J=5.49 Hz, 2H) 7.49 (t, J=7.63Hz, 1H) 7.69-7.73 (m, 1H) 7.85-7.91 (m, 1H) 8.06 (d, J=7.63 Hz, 1H)8.10-8.17 (m, 1H) 8.27 (t, J=5.49 Hz, 1H) 12.01 (s, 1H).

EXAMPLE 961-Acetyl-N-((5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl)piperidine-4-carboxamide

A mixture of Example 92B (0.1 g, 0.47 mmol) and1-acetylpiperidine-4-carbonyl chloride (0.089 g, 0.47 mmol) in DMF (1mL) and pyridine (1 mL) was stirred overnight. The precipitated solidswere filtered and washed with H₂O and Et₂O then dried well. ¹H NMR (500MHz, DMSO-d₆) δ ppm 1.32-1.41 (m, 1H) 1.46-1.55 (m, 1H) 1.69 (t, J=14.19Hz, 2H) 1.98 (s, 3H) 2.35-2.41 (m, 1H) 2.52-2.60 (m, 1H) 3.00 (dd,J=12.21, 10.68 Hz, 1H) 3.80 (d, J=13.73 Hz, 1H) 4.20 (d, J=5.80 Hz, 2H)4.33 (d, J=13.43 Hz, 1H) 7.47-7.52 (m, 1H) 7.70 (s, 1H) 7.86-7.92 (m,1H) 8.06 (d, J=8.24 Hz, 1H) 8.15 (dd, J=7.93, 1.22 Hz, 1H) 8.24 (t,J=5.49 Hz, 1H) 11.97 (s, 1H).

EXAMPLE 972-oxo-2-{[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]amino}ethylacetate

The title compound was prepared as described in Example 96, substituting2-chloro-2-oxoethyl acetate for 1-acetylpiperidine-4-carbonyl chloride.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.09 (s, 3H) 4.25 (d, J=5.83 Hz, 2H)4.47 (s, 2H) 7.47-7.52 (m, 1H) 7.70 (s, 1H) 7.85-7.91 (m, 1H) 8.07 (d,J=8.29 Hz, 1H) 8.15 (d, J=7.98 Hz, 1H) 8.36 (t, J=5.52 Hz, 1H)

EXAMPLE 98 3-(Pyrrolidin-1-ylmethyl)pyrazolo[1,5-a]quinazolin-5-(4H)-one

A mixture of Example 92B (0.1 g, 0.47 mmol), 1-bromo-4-chlorobutane(0.08 g, 0.47 mmol) and sodium ethoxide (0.032 g, 0.47 mmol) in EtOH (2mL) was stirred overnight then evaporated. The residue was purified byHPLC on a C18 column with 0-100% CH₃CN/H₂O/0.1% TFA to provide thedesired product as the trifluoroacetate salt. ¹H NMR (500 MHz, DMSO-d₆)δ ppm 1.84 (ddd, J=6.87, 3.66, 3.51 Hz, 3H) 3.08-3.10 (m, 5H) 4.09 (s,2H) 7.54 (t, J=7.63 Hz, 1H) 7.90-7.99 (m, 2H) 8.11 (d, J=8.54 Hz, 1H)8.18 (d, J=7.93 Hz, 1H)

EXAMPLE 991-((5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl)pyrrolidine-2,5-dione

A mixture Example 95 (0.05 g, 0.44mmol) and CDI (0.039 g, 0.24 mmol) inDMF (2 mL) was stirred overnight at ambient temperature. The mixture wasevaporated and purified by chromatography on silica gel with 10%MeOH/CH₂Cl₂ to provide the desired product. ¹H NMR (500 MHz, DMSO-d₆) δppm 2.66 (s, 4H) 4.59 (s, 2H) 7.47-7.54 (m, 1H) 7.62 (s, 1H) 7.88 (s,1H) 8.05 (d, J=8.24 Hz, 1H) 8.16 (d, J=7.02 Hz, 1H)

EXAMPLE 100N-((5-Oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl)acetamide

A mixture of Example 92B (0.1 g, 0.47 mmol), acetic anhydride (0.048 g,0.47 mmol) and diisopropyl ethylamine (0.2 ml, 1.15 mmol) in MeOH (2 ml)was heated to 40° C. overnight. The mixture was evaporated and purifiedby chromatography on silica gel with 10% MeOH/CH₂Cl₂ to provide thedesired product. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.85 (s, 3H) 4.19 (d,J=5.49 Hz, 2H) 7.49 (t, J=7.48 Hz, 1H) 7.73 (s, 1H) 7.88 (t, J=7.48 Hz,1H) 8.06 (d, J=8.24 Hz, 1H) 8.15 (d, J=7.63 Hz, 1H) 8.26 (s, 1H)

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃ and R₄are independently selected from the group consisting of hydrogen,alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy,haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NR_(A)R_(B), and(NR_(A)R_(B))carbonyl; X is aryl, arylalkyl, alkyl, heteroaryl,heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,heterocyclecarbonyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,NR_(C)R_(D), (NR_(C)R_(D))carbonyl, (NR_(C)R_(D))alkyl,(NR_(C)R_(D))carbonylalkyl, or -alkyl-CO₂G₁; wherein if X is aryl,arylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle,heterocyclealkyl, heterocyclecarbonyl, cycloalkyl, or cycloalkylalkylthen X may be unsubstituted or substituted with 1, 2, 3, 4, or 5substituents, Z, independently selected from the group consisting ofalkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy,alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl,arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylalkyl,heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle,heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl,heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR_(C)R_(D),(NR_(C)R_(D))alkyl, (NR_(C)R_(D))carbonyl, (NR_(C)R_(D))carbonylalkyl,and oxo; wherein the aryl and the heteroaryl moieties of Z areindependently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, formyl,halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties of Zare independently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, oxo, formyl,halogen, and haloalkyl; G₁ is hydrogen, alkyl, alkenyl, haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl,heterocycle, or heterocyclealkyl; wherein the aryl, the aryl moiety ofarylalkyl, the heteroaryl, the heteroaryl moiety of heteroarylakyl, thecycloalkyl, the cycloalkyl moiety of cycloalkylalkyl, the heterocycle,and the heterocycle moiety of heterocyclealkyl are independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl,alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,carboxy, carboxyalkyl, hydroxy, hydroxyalkyl, NR_(A)R_(B),(NR_(A)R_(B))alkyl, (NR_(A)R_(B))carbonyl, (NR_(A)R_(B))carbonylalkyl,and oxo; R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen, alkyl, alkylcarbonyl,alkylcarbonyloxyalkylcarbonyl, arylcarbonyl, aryl, arylalkyl,arylalkylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl,cycloalkylalkyl, haloalkyl, haloalkylcarbonyl, heteroaryl,heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,heterocyclecarbonyl, heterocyclealkylcarbonyl, (NR_(A)R_(B))alkyl, and(NR_(A)R_(B))alkylcarbonyl; wherein if R_(C) or R_(D) are aryl,arylalkyl, arylalkylcarbonyl, arylcarbonyl, cycloalkyl, cycloalkylalkyl,heteroalyl, heteroarylalkyl, heteroarylcarbonyl, heterocycle,heterocyclealkyl, heterocyclecarbonyl, or heterocyclealkylcarbonyl, thenR_(C) or R_(D) may be unsubstituted or substituted with 1, 2, 3, 4, or 5substituents independently selected from the group consisting of alkyl,alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, oxo, alkoxy,alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkylcarbonyl, andarylalkoxycarbonyl; R_(A) and R_(B) are independently selected from thegroup consisting of hydrogen, alkyl, haloalkyl, and alkylcarbonyl; and nis
 1. 2. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃ and R₄are hydrogen; X is aryl, arylalkyl, alkyl, heteroaryl,heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl,hydroxyalkyl, cycloalkyl, (NR_(C)R_(D))carbonyl, or (NR_(C)R_(D))alkyl;wherein if X is aryl, arylalkyl, heteroaryl, heterocycle,heterocyclealkyl, heterocyclecarbonyl, or cycloalkyl, then X may beunsubstituted or substituted with 1 or 2 substituents, Z, independentlyselected from the group consisting of alkyl, nitro, —CN, halogen,alkoxy, alkoxycarbonyl, aryl, arylalkyl, arylalkoxycarbonyl, carboxy,cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycle,heterocyclealkyl, heterocyclealkylcarbonyl, NR_(C)R_(D),(NR_(C)R_(D))alkyl, (NR_(C)R_(D))carbonyl, and oxo; wherein the aryl andthe heteroaryl moieties of Z are independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of alkyl, formyl, halogen, and haloalkyl, and the heterocycleand cycloalkyl moieties of Z are independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of alkyl, oxo, formyl, halogen, and haloalkyl; R_(C) andR_(D) are independently selected from the group consisting of hydrogen,alkyl, alkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, aryl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl,cycloalkyl, haloalkyl, haloalkylcarbonyl, heteroaryl,heteroarylcarbonyl, heterocyclealkyl, heterocyclecarbonyl,heterocyclealkylcarbonyl, (NR_(A)R_(B))alkyl, and(NR_(A)R_(B))alkylcarbonyl; wherein if R_(C) or R_(D) arearylalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclealkyl,heterocyclecarbonyl, or heterocyclealkylcarbonyl, then R_(C) or R_(D)may be unsubstituted or substituted with one substituent selected fromthe group consisting of alkoxy, alkylcarbonyl and arylalkoxycarbonyl;R_(A) and R_(B) are independently selected from the group consisting ofhydrogen, alkyl, and alkylcarbonyl; and n is
 1. 3. A compound of Formula(II)

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃ and R₄are independently selected from the group consisting of hydrogen,alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy,haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NR_(A)R_(B), and(NR_(A)R_(B))carbonyl; X is aryl, arylalkyl, alkyl, heteroaryl,heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,heterocyclecarbonyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,NR_(C)R_(D), (NR_(C)R_(D))carbonyl, (NR_(C)R_(D))alkyl,(NR_(C)R_(D))carbonylalkyl, or -alkyl-CO₂G₁; wherein if X is aryl,arylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle,heterocyclealkyl, heterocyclecarbonyl, cycloalkyl, or cycloalkylalkylthen X may be unsubstituted or substituted with 1, 2, 3, 4, or 5substituents, Z, independently selected from the group consisting ofalkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy,alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl,arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylalkyl,heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle,heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl,heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR_(C)R_(D),(NR_(C)R_(D))alkyl, (NR_(C)R_(D))carbonyl, (NR_(C)R_(D))carbonylalkyl,and oxo; wherein the aryl and the heteroaryl moieties of Z areindependently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, formyl,halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties of Zare independently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, oxo, formyl,halogen, and haloalkyl; G₁ is hydrogen, alkyl, alkenyl, haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl,heterocycle, or heterocyclealkyl; wherein the aryl, the aryl moiety ofarylalkyl, the heteroaryl, the heteroaryl moiety of heteroarylakyl, thecycloalkyl, the cycloalkyl moiety of cycloalkylalkyl, the heterocycle,and the heterocycle moiety of heterocyclealkyl are independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl,alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,carboxy, carboxyalkyl, hydroxy, hydroxyalkyl, NR_(A)R_(B),(NR_(A)R_(B))alkyl, (NR_(A)R_(B))carbonyl, (NR_(A)R_(B))carbonylalkyl,and oxo; R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen, alkyl, alkylcarbonyl,alkylcarbonyloxyalkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl,cycloalkylalkyl, haloalkyl, haloalkylcarbonyl, heteroaryl,heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,heterocyclecarbonyl, heterocyclealkylcarbonyl, (NR_(A)R_(B))alkyl, and(NR_(A)R_(B))alkylcarbonyl; wherein if R_(C) or R_(D) are aryl,arylalkyl, arylalkylcarbonyl, arylcarbonyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle,heterocyclealkyl, heterocyclecarbonyl, or heterocyclealkylcarbonyl, thenR_(C) or R_(D) may be unsubstituted or substituted with 1, 2, 3, 4, or 5substituents independently selected from the group consisting of alkyl,alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, oxo, alkoxy,alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkylcarbonyl, andarylalkoxycarbonyl; and R_(A) and R_(B) are independently selected fromthe group consisting of hydrogen, alkyl, haloalkyl, and alkylcarbonyl.4. A compound of Formula (III)

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃ and R₄are independently selected from the group consisting of hydrogen,alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy,haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NR_(A)R_(B), and(NR_(A)R_(B))carbonyl; X is aryl, arylalkyl, alkyl, heteroaryl,heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,heterocyclecarbonyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl,NR_(C)R_(D), (NR_(C)R_(D))carbonyl, (NR_(C)R_(D))alkyl,(NR_(C)R_(D))carbonylalkyl, or -alkyl-CO₂G₁; wherein if X is aryl,arylalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle,heterocyclealkyl, heterocyclecarbonyl, cycloalkyl, or cycloalkylalkylthen X may be unsubstituted or substituted with 1, 2, 3, 4, or 5substituents, Z, independently selected from the group consisting ofalkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy,alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl,arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylalkyl,heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle,heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl,heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR_(C)R_(D),(NR_(C)R_(D))alkyl, (NR_(C)R_(D))carbonyl, (NR_(C)R_(D))carbonylalkyl,and oxo; wherein the aryl and the heteroaryl moieties of Z areindependently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, formyl,halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties of Zare independently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, oxo, formyl,halogen, and haloalkyl; G₁ is hydrogen, alkyl, alkenyl, haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl,heterocycle, or heterocyclealkyl; wherein the aryl, the aryl moiety ofarylalkyl, the heteroaryl, the heteroaryl moiety of heteroarylakyl, thecycloalkyl, the cycloalkyl moiety of cycloalkylalkyl, the heterocycle,and the heterocycle moiety of heterocyclealkyl are independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy, alkylcarbonyl,alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,carboxy, carboxyalkyl, hydroxy, hydroxyalkyl, NR_(A)R_(B),(NR_(A)R_(B))alkyl, (NR_(A)R_(B))carbonyl, (NR_(A)R_(B))carbonylalkyl,and oxo; R_(C) and R_(D) are independently selected from the groupconsisting of hydrogen, alkyl, alkylcarbonyl,alkylcarbonyloxyalkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl,carboxyalkyl, carboxyalkylcarbonyl, cycloalkyl, cycloalkylalkyl,haloalkyl, haloalkylcarbonyl, heteroaryl, heteroarylalkyl,heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl,heterocyclealkylcarbonyl, (NR_(A)R_(B))alkyl, and(NR_(A)R_(B))alkylcarbonyl; wherein if R_(C) or R_(D) are aryl,arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heteroaryl,heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl,heterocyclecarbonyl, or heterocyclealkylcarbonyl, then R_(C) or R_(D)may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, nitro, —CN, halogen, haloalkyl, oxo, alkoxy, alkylcarbonyl,alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryl, arylalkyl, arylalkoxy, arylalkylcarbonyl, and arylalkoxycarbonyl;and R_(A) and R_(B) are independently selected from the group consistingof hydrogen, alkyl, haloalkyl, and alkylcarbonyl.
 5. A compoundaccording to claim 3 wherein X is aryl or arylalkyl wherein the aryl orarylalkyl may be unsubstituted or substituted with 1, 2, 3, 4, or 5substituents, Z, independently selected from the group consisting ofalkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy,alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl,arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylalkyl,heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle,heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl,heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR_(C)R_(D),(NR_(C)R_(D))alkyl, (NR_(C)R_(D))carbonyl, and(NR_(C)R_(D))carbonylalkyl; wherein the aryl and the heteroaryl moietiesof Z are independently unsubstituted or substituted with 1, 2, 3, 4, or5 substituents selected from the group consisting of alkyl, formyl,halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties of Zare independently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, oxo, formyl,halogen, and haloalkyl.
 6. A compound according to claim 3 wherein X isheteroaryl which may be unsubstituted or substituted with 1, 2, 3, 4, or5 substituents, Z, independently selected from the group consisting ofalkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy,alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl,arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylalkyl,heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle,heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl,heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR_(C)R_(D),(NR_(C)R_(D))alkyl, (R_(C)R_(D))carbonyl, and(NR_(C)R_(D))carbonylalkyl; wherein the aryl and the heteroaryl moietiesof Z are independently unsubstituted or substituted with 1, 2, 3, 4, or5 substituents selected from the group consisting of alkyl, formyl,halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties of Zare independently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, oxo, formyl,halogen, and haloalkyl.
 7. A compound according to claim 3 wherein X isheterocycle or heterocyclealkyl wherein the heterocycle orheterocyclealkyl may be unsubstituted or substituted with 1, 2, 3, 4, or5 substituents, Z, independently selected from the group consisting ofalkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy,alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl,arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylalkyl,heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle,heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl,heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR_(C)R_(D),(NR_(C)R_(D))alkyl, (NR_(C)R_(D))carbonyl, (NR_(C)R_(D))carbonylalkyl,and oxo; wherein the aryl and the heteroaryl moieties of Z areindependently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, formyl,halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties of Zare independently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, oxo, formyl,halogen, and haloalkyl.
 8. A compound according to claim 4 wherein X isheteroarylcarbonyl, heterocyclealkyl, heterocyclecarbonyl, hydroxyalkyl,(NR_(C)R_(D))carbonyl, (NR_(C)R_(D))alkyl, or aryl wherein if X isheteroarylcarbonyl, heterocyclealkyl, heterocyclecarbonyl, or aryl, thenX may be unsubstituted or substituted with 1, 2, 3, 4, or 5substituents, Z, independently selected from the group consisting ofalkyl, alkenyl, alkynyl, nitro, —CN, halogen, haloalkyl, alkoxy,alkylcarbonyl, alkylcarbonylalkyl, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryl, arylalkyl, arylalkoxy, arylalkoxycarbonyl,arylalkylcarbonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkoxy, cycloalkylcarbonyl, heteroaryl, heteroarylalkyl,heteroarylcarbonyl, heteroarylcarbonylalkyl, heterocycle,heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl,heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, NR_(C)R_(D),(NR_(C)R_(D))alkyl, (NR_(C)R_(D))carbonyl, (NR_(C)R_(D))carbonylalkyl,and oxo; wherein the aryl and the heteroaryl moieties of Z areindependently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, formyl,halogen, and haloalkyl, and the heterocycle and cycloalkyl moieties of Zare independently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, oxo, formyl,halogen, and haloalkyl.
 9. A compound according to claim 1 wherein R₁,R₂, R₃ and R₄ are hydrogen.
 10. A compound selected from the groupconsisting of 3-phenyl-4H-pyrazolo[1,5-a]quinazolin-5-one;3-(4-chloro-phenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-phenyl-4H-pyrazolo[1,5-a]quinazolin-5-one;2-tert-butyl-4H-pyrazolo[1,5-a]quinazolin-5-one;2-furan-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;2-thiophen-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(4-methoxyphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(3-nitrophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(3-chlorophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-biphenyl-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;2-biphenyl-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(3-aminophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(2-chlorophenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-[3-(2-aminoethylamino)phenyl]-4H-pyrazolo[1,5-a]quinazolin-5-one;N-{2-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenylamino]ethyl}-acetamide;N-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]acetamide;benzyl 4-({acetyl[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]amino}methyl)piperidine-1-carboxylate;2-[3-(2-dimethylaminoethylamino)phenyl]-4H-pyrazolo[1,5-a]quinazolin-5-one;2-piperidin-3-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-methylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-ethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-isobutylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-cyclopropylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-[1-(3-piperidin-1-ylpropionyl)piperidin-3-yl]-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-propylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-benzylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-cyclopentylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-pyridin-4-ylmethylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-isopropylpiperidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one; methyl4-(5-oxo-4, 5-dihydropyrazolo[1,5-a]quinazolin-2-yl)benzoate;2-(3-fluoro-4-morpholin-4-ylphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-cyclopropyl-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-benzylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;N-[3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)phenyl]-3-piperidin-1-ylpropionamide;2-piperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(4-pyrrolidin-1-ylmethylphenyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-methylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-ethylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-propylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-cyclopropylmethylpiperidin-4-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-isobutylpiperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-isopropylpiperidin-4-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;2-pyrrolidin-3-yl-4H-pyrazolo[1,5-a]quinazolin-5-one; benzyl 3-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)pyrrolidine-1-carboxylate;2-(1-methylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-ethylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-cyclopropylmethylpyrrolidin-3-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-piperidin-2-yl-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-methylpiperidin-2-yl)-4H-pyrazolo[1,5-a]quinazolin-5-one;(S)-2-acetylamino-4-methyl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)pentanamide;(R)-2-methoxy-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-2-phenylacetamide;N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)isonicotinamide;N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-3-piperidin-1-yl-propionamide;N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-3-pyrrolidin-1-yl-propionamide;2-morpholin-4-yl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)acetamide;3-morpholin-4-yl-N-(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-ylmethyl)-propionamide;2-phenethyl-4H-pyrazolo[1,5-a]quinazolin-5-one;2-benzyl-4H-pyrazolo[1,5-a]quinazolin-5-one;2-piperidin-4-ylmethyl-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(1-methylpiperidin-4-ylmethyl)-4H-pyrazolo[1,5-a]quinazolin-5-one;2-(3-bromobenzyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzonitrile;2-[3-(aminomethyl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one;2-(3-pyridin-3-ylbenzyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;2-[3-(2-oxopyrrolidin-1-yl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one;3′-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]-1,1′-biphenyl-2-carbaldehyde;2-[3-(2-fluoropyridin-4-yl)benzyl]pyrazolo[1,5-a]quinazolin-5(4H)-one;methyl3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzoate;3-[(4-methylpiperazin-1-yl)carbonyl]pyrazolo[1,5-a]quinazolin-5(4H)-one;3-(pyrrolidin-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;N,N-dimethyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;3-(piperidin-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;N-cyclopropyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;N-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;N-ethyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;N-benzyl-5-oxo-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;5-oxo-N-(2-phenylethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;3-(azepan-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;3-(morpholin-4-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;3-(piperazin-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;N-cyclohexyl-5-oxo-4, 5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;3-(1H-imidazol-1-ylcarbonyl)pyrazolo[1,5-a]quinazolin-S (4H)-one;5-oxo-N-(piperidin-4-ylmethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;3-{[3-(aminomethyl)piperidin-1-yl]carbonyl}pyrazolo[1,5-a]quinazolin-5(4H)-one;5-oxo-N-phenyl-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;4-{[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)carbonyl]amino}butanoicacid; 3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzoicacid;5-oxo-N-(2-piperidin-1-ylethyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide;3-(hydroxymethyl)pyrazolo[1,5-a]quinazolin -5-(4H)-one;3-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-2-yl)methyl]benzamide;3-(aminomethyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;N-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]glycine;4-chloro-N-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]butanamide;4-oxo-4-{[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]amino}butanoicacid;1-acetyl-N-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]piperidine-4-carboxamide;2-oxo-2-{[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]amino}ethylacetate; 3-(pyrrolidin-1-ylmethyl)pyrazolo[1,5-a]quinazolin-5(4H)-one;1-[(5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl]pyrrolidine-2,5-dione;andN-((5-oxo-4,5-dihydropyrazolo[1,5-a]quinazolin-3-yl)methyl)acetamide; ora pharmaceutically acceptable salt thereof.
 11. A method of treatinginflammation in a mammal in recognized need of such treatment comprisingadministering to the mammal a therapeutically acceptable amount of acompound of Formula (I) of claim 1 or a pharmaceutically acceptable saltthereof.
 12. A method of treating sepsis in a mammal in recognized needof such treatment comprising administering to the mammal atherapeutically acceptable amount of a compound of Formula (I) of claim1 or a pharmaceutically acceptable salt thereof.
 13. A method oftreating septic shock in a mammal in recognized need of such treatmentcomprising administering to the mammal a therapeutically acceptableamount of a compound of Formula (I) of claim 1 or a pharmaceuticallyacceptable salt thereof.
 14. A method of treating cancer in a mammal inrecognized need of such treatment comprising administering to the mammala therapeutically acceptable amount of a compound of Formula (I) ofclaim 1 or a pharmaceutically acceptable salt thereof.
 15. Apharmaceutical composition comprising a compound of Formula (I) of claim1 or a pharmaceutically acceptable salt thereof, in combination with atherapeutically acceptable carrier.